Sulfonyl divalent aryl or heteroaryl hydroxamic acid compounds

ABSTRACT

A sulfonyl divalent aromatic or heteroaromatic ring hydroxamic acid compound that inter alia inhibits matrix metalloprotease activity is disclosed as are a treatment process that comprises administering a contemplated sulfonyl divalent aromatic or heteroaromatic ring hydroxamic acid compound in a MMP enzyme-inhibiting effective amount to a host having a condition associated with pathological matrix metalloprotease activity.

DESCRIPTION

[0001] 1. Technical Field

[0002] This invention is directed to proteinase (protease) inhibitors,and more particularly to sulfonyl divalent aryl or heteroaryl hydroxamicacid compounds that, inter alia, inhibit the activity of matrixmetalloproteinases, compositions of those inhibitors, intermediates forthe syntheses of those compounds, processes for the preparation of thecompounds and processes for treating pathological conditions associatedwith pathological matrix metalloproteinase activity.

[0003] 2. Background of the Invention

[0004] Connective tissue, extracellular matrix constituents and basementmembranes are required components of all mammals. These components arethe biological materials that provide rigidity, differentiation,attachments and, in some cases, elasticity to biological systemsincluding human beings and other mammals. Connective tissues componentsinclude, for example, collagen, elastin, proteoglycans, fibronectin andlaminin. These biochemicals makeup, or are components of structures,such as skin, bone, teeth, tendon, cartilage, basement membrane, bloodvessels, cornea and vitreous humor.

[0005] Under normal conditions, connective tissue turnover and/or repairprocesses are controlled and in equilibrium. The loss of this balancefor whatever reason leads to a number of disease states. Inhibition ofthe enzymes responsible loss of equilibrium provides a control mechanismfor this tissue decomposition and, therefore, a treatment for thesediseases.

[0006] Degradation of connective tissue or connective tissue componentsis carried out by the action of proteinase enzymes released fromresident tissue cells and/or invading inflammatory or tumor cells. Amajor class of enzymes involved in this function are the zincmetalloproteinases (metalloproteases, or MMPs).

[0007] The metalloprotease enzymes are divided into classes with somemembers having several different names in common use. Examples are:collagenase I (MMP-1, fibroblast collagenase; EC 3.4.24.3); collagenaseII (MMP-8, neutrophil collagenase; EC 3.4.24.34), collagenase III(MMP-13), stromelysin 1 (MMP-3; EC 3.4.24.17), stromelysin 2 (MMP-10; EC3.4.24.22), proteoglycanase, matrilysin (MMP-7), gelatinase A (MMP-2, 72kDa gelatinase, basement membrane collagenase; EC 3.4.24.24), gelatinaseB (MMP-9, 92 kDa gelatinase; EC 3.4.24.35), stromelysin 3 (MMP-11),metalloelastase (MMP-12, HME, human macrophage elastase) and membraneMMP (MMP-14). MMP is an abbreviation or acronym representing the termMatrix Metalloprotease with the attached numerals providingdifferentiation between specific members of the MMP group.

[0008] The uncontrolled breakdown of connective tissue bymetalloproteases is a feature of many pathological conditions. Examplesinclude rheumatoid arthritis, osteoarthritis, septic arthritis; corneal,epidermal or gastric ulceration; tumor metastasis, invasion orangiogenesis; periodontal disease; proteinuria; Alzheimer's Disease;coronary thrombosis and bone disease. Defective injury repair processescan also occur. This can produce improper wound healing leading to weakrepairs, adhesions and scarring. These latter defects can lead todisfigurement and/or permanent disabilities as with post-surgicaladhesions.

[0009] Matrix metalloproteases are also involved in the biosynthesis oftumor necrosis factor (TNF) and inhibition of the production or actionof TNF and related compounds is an important clinical disease treatmentmechanism. TNF-α, for example, is a cytokine that at present is thoughtto be produced initially as a 28 kD cell-associated molecule. It isreleased as an active, 17 kD form that can mediate a large number ofdeleterious effects in vitro and in vivo. For example, TNF can causeand/or contribute to the effects of inflammation, rheumatoid arthritis,autoimmune disease, multiple sclerosis, graft rejection, fibroticdisease, cancer, infectious diseases, malaria, mycobacterial infection,meningitis, fever, psoriasis, cardiovascular/pulmonary effects such aspost-ischemic reperfusion injury, congestive heart failure, hemorrhage,coagulation, hyperoxic alveolar injury, radiation damage and acute phaseresponses like those seen with infections and sepsis and during shocksuch as septic shock and hemodynamic shock. Chronic release of activeTNF can cause cachexia and anorexia. TNF can be lethal.

[0010] TNF-α convertase is a metalloproteinase involved in the formationof active TNF-α. Inhibition of TNF-α convertase inhibits production ofactive TNF-α. Compounds that inhibit both MMPs activity have beendisclosed in WIPO International Publication Nos. WO 94/24140, WO94/02466 and WO 97/20824. There remains a need for effective MMP andTNF-α convertase inhibiting agents. Compounds that inhibit MMPs such ascollagenase, stromelysin and gelatinase have been shown to inhibit therelease of TNF (Gearing et al. Nature 376, 555-557 (1994), McGeehan etal., Nature 376, 558-561 (1994)).

[0011] MMPs are involved in other biochemical processes in mammals aswell. Included is the control of ovulation, post-partum uterineinvolution, possibly implantation, cleavage of APP (β-Amyloid PrecursorProtein) to the amyloid plaque and inactivation of α₁-protease inhibitor(α₁-PI). Inhibition of these metalloproteases permits the control offertility and the treatment or prevention of Alzheimers Disease. Inaddition, increasing and maintaining the levels of an endogenous oradministered serine protease inhibitor drug or biochemical such as α₁-PIsupports the treatment and prevention of diseases such as emphysema,pulmonary diseases, inflammatory diseases and diseases of aging such asloss of skin or organ stretch and resiliency.

[0012] Inhibition of selected MMPs can also be desirable in otherinstances. Treatment of cancer and/or inhibition of metastasis and/orinhibition of angiogenesis are examples of approaches to the treatmentof diseases wherein the selective inhibition of stromelysin (MMP-3),gelatinase (MMP-2), gelatinase B (MMP-9) or collagenase III (MMP-13) arethe relatively most important enzyme or enzymes to inhibit especiallywhen compared with collagenase I (MMP-1). A drug that does not inhibitcollagenase I can have a superior therapeutic profile. Osteoarthritis,another prevalent disease wherein it is believed that cartilagedegradation in inflamed joints is at least partially caused by MMP-13released from cells such as stimulated chrondrocytes, may be besttreated by administration of drugs one of whose modes of action isinhibition of MMP-13. See, for example, Mitchell et al., J. Clin.Invest., 97:761-768 (1996) and Reboul et al., J. Clin. Invest.,97:2011-2019 (1996).

[0013] Inhibitors of metalloproteases are known. Examples includenatural biochemicals such as tissue inhibitor of metalloproteinase(TIMP), α₂-macroglobulin and their analogs or derivatives. These arehigh molecular weight protein molecules that form inactive complexeswith metalloproteases. A number of smaller peptide-like compounds thatinhibit metalloproteases have been described. Mercaptoamide peptidylderivatives have shown ACE inhibition in vitro and in vivo. Angiotensinconverting enzyme (ACE) aids in the production of angiotensin II, apotent pressor substance in mammals and inhibition of this enzyme leadsto the lowering of blood pressure.

[0014] Thiol group-containing amide or peptidyl amide-basedmetalloprotease (MMP) inhibitors are known as is shown in, for example,WO95/12389, WO96/11209 and U.S. Pat. No. 4,595,700. Hydroxamategroup-containing MMP inhibitors are disclosed in a number of publishedpatent applications such as WO 95/29892, WO 97/24117, WO 97/49679 and EP0 780 386 that disclose carbon back-boned compounds, and WO 90/05719, WO93/20047, WO 95/09841 and WO 96/06074 that disclose hydroxamates thathave a peptidyl back-bones or peptidomimetic back-bones, as does thearticle by Schwartz et al., Progr. Med. Chem., 29:271-334(1992) andthose of Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997) andDenis et al., Invest. New Drugs, 15(3): 175-185 (1997).

[0015] One possible problem associated with known MMP inhibitors is thatsuch compounds often exhibit the same or similar inhibitory effectsagainst each of the MMP enzymes. For example, the peptidomimetichydroxamate known as batimastat is reported to exhibit IC₅₀ values ofabout 1 to about 20 nanomolar (nM) against each of MMP-1, MMP-2, MMP-3,MMP-7, and MMP-9. Marimastat, another peptidomimetic hydroxamate wasreported to be another broad-spectrum MMP inhibitor with an enzymeinhibitory spectrum very similar to batimastat, except that marimastatexhibited an IC₅₀ value against MMP-3 of 230 nM. Rasmussen et al.,Pharmacol. Ther., 75(1): 69-75 (1997).

[0016] Meta analysis of data from Phase I/II studies using marimastat inpatients with advanced, rapidly progressive, treatment-refractory solidtumor cancers (colorectal, pancreatic, ovarian, prostate) indicated adose-related reduction in the rise of cancer-specific antigens used assurrogate markers for biological activity. Although marimastat exhibitedsome measure of efficacy via these markers, toxic side effects werenoted. The most common drug-related toxicity of marimastat in thoseclinical trials was musculoskeletal pain and stiffness, often commencingin the small joints in the hands, spreading to the arms and shoulder. Ashort dosing holiday of 1-3 weeks followed by dosage reduction permitstreatment to continue. Rasmussen et al., Pharmacol. Ther., 75(1): 69-75(1997). It is thought that the lack of specificity of inhibitory effectamong the MMPs may be the cause of that effect.

[0017] In view of the importance of hydroxamate MMP inhibitor compoundsin the treatment of several diseases and the lack of enzyme specificityexhibited by two of the more potent drugs now in clinical trials, itwould be a great benefit if hydroxamates of greater enzyme specificitycould be found. This would be particularly the case if the hydroxamateinhibitors exhibited strong inhibitory activity against one or more ofMMP-2, MMP-9 or MMP-13 that are associated with several pathologicalconditions, while at the same time exhibiting limited inhibition ofMMP-1, an enzyme that is relatively ubiquitous and as yet not associatedwith any pathological condition. The disclosure that follows describesone family of hydroxamate MMP inhibitors that exhibit those desirableactivities

BRIEF SUMMARY OF THE INVENTION

[0018] The present invention is directed to a family of molecules thatamong other properties inhibit matrix metalloprotease (MMP) activity,and particularly inhibit the activity of one or more of MMP-2, MMP-9, orMMP-13, while generally exhibiting little activity against MMP-1. Thepresent invention is also directed to processes for preparing acontemplated compound and for treating a mammal having a conditionassociated with pathological matrix metalloprotease activity.

[0019] Briefly, one embodiment of the present invention is directed to asulfonyl divalent aryl or heteroaryl hydroxamic acid compound that canact as a matrix metalloprotease enzyme inhibitor. That compoundcorresponds in structure to Formula I.

[0020] wherein

[0021] y and z are each zero or one and the sum of z+y is one;

[0022] the ring structure W is a 5- or 6-membered divalent aromatic orheteroaromatic ring;

[0023] X is —CH₂— or —NH—;

[0024] R¹ is a substituent containing a 5- or 6-memberedcyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bondeddirectly to the depicted SO₂-group and having a length greater thanabout that of a hexyl group and less than about that of a eicosyl group,said R¹ defining a three-dimensional volume, when rotated about an axisdrawn through the SO₂-bonded 1-position and the 4-position of a6-membered ring radical or drawn through the SO₂-bonded 1-position andthe center of 3,4-bond of a 5-membered ring radical, whose widestdimension in a direction transverse to the axis of rotation is aboutthat of one furanyl ring to about that of two phenyl rings;

[0025] R² and R³ are independently hydrido, C₁-C₄ hydrocarbyl, hydroxylor amino, or R² and R³ together with the depicted carbon atom to whichthey are bonded form a 6-membered heterocyclic ring in which theheteroatom is oxygen, sulfur or nitrogen, said heteroatom beingoptionally substituted with one or two oxygens when sulfur and beingoptionally substituted with a moiety selected from the group consistingof a C₁-C₄ hydrocarbyl, C₃-C₆ cyclohydrocarbyl, C₁-C₄ acylhydrocarbyl,and sulfonyl C₁-C₄ hydrocarbyl group when nitrogen.

[0026] In preferred embodiments, a contemplated compound corresponds instructure to Formula IA,

[0027] wherein W, X, y, z, R² and R³ are as defined above, Ph is phenylsubstituted at the 4-position with substituent R⁴ that is definedhereinafter.

[0028] A process for treating a host mammal having a conditionassociated with pathological matrix metalloprotease activity is alsocontemplated. That process comprises administering a compound describedhereinbefore in an enzyme-inhibiting effective amount to a mammalianhost having such a condition. The use of repeated administrations isparticularly contemplated.

[0029] Among the several benefits and advantages of the presentinvention are the provision of compounds and compositions effective asinhibitors of matrix metalloproteinase activity, and the provision ofsuch compounds and compositions that are effective for the inhibition ofmetalloproteinases implicated in diseases and disorders involvinguncontrolled breakdown of connective tissue.

[0030] More particularly, a benefit of this invention is the provisionof a compound and composition effective for inhibitingmetalloproteinases, particularly MMP-13 and/or MMP-2, associated withpathological conditions such as, for example, rheumatoid arthritis,osteoarthritis, septic arthritis, corneal, epidermal or gastriculceration, tumor metastasis, invasion or angiogenesis, periodontaldisease, proteinuria, Alzheimer's Disease, coronary thrombosis and bonedisease.

[0031] An advantage of the invention is the provision of a method forpreparing such compositions. Another benefit is the provision of amethod for treating a pathological condition associated with abnormalmatrix metalloproteinase activity.

[0032] Another advantage of the invention is the provision of compounds,compositions and methods effective for treating such pathologicalconditions by selective inhibition of a metalloproteinase such as MMP-13and MMP-2 associated with such conditions with minimal side effectsresulting from inhibition of other proteinases such as MMP-1, whoseactivity is necessary or desirable for normal body function.

[0033] Still further benefits and advantages of the invention will beapparent to the skilled worker from the disclosure that follows.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0034] In accordance with the present invention, it has been found thatcertain sulfonyl divalent aryl or heteroaryl hydroxamic acids(hydroxamates) are effective, inter alia, for inhibition of matrixmetalloproteinases (“MMPs”) believed to be associated with uncontrolledor otherwise pathological breakdown of connective tissue. In particular,it has been found that these certain sulfonyl divalent aryl orheteroaryl hydroxamic acid compounds are effective for inhibition ofcollagenase III (MMP-13) and also gelatinase A (MMP-2), which can beparticularly destructive to tissue if present or generated in abnormalquantities or concentrations, and thus exhibit a pathological activity.

[0035] Moreover, it has been discovered that many of these aromaticsulfonyl alpha-cycloamino hydroxamic acids are selective in theinhibition of MMPs associated with diseased conditions without excessiveinhibition of other collagenases essential to normal bodily functionsuch as tissue turnover and repair. More particularly, it has been foundthat particularly preferred the sulfonyl divalent aryl or heteroarylhydroxamic acid compounds are particularly active in inhibiting ofMMP-13 and/or MMP-2, while having a limited or minimal effect on MMP-1.This point is discussed in detail hereinafter and is illustrated in theInhibition Table hereinafter.

[0036] One embodiment of the present invention is directed to a sulfonyldivalent aryl or heteroaryl hydroxamic acid compound that can act as amatrix metalloprotease enzyme inhibitor. That compound corresponds instructure to Formula I

[0037] wherein

[0038] y and z are each zero or one and the sum of z+y is one;

[0039] the ring structure W is a 5- or 6-membered divalent aromatic orheteroaromatic ring;

[0040] X is —CH₂— or —NH—;

[0041] R¹ is a substituent containing a 5- or 6-memberedcyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bondeddirectly to the depicted SO₂-group and having a length equivalent to alength that is greater than about that of a fully extended hexyl groupand less than about that of a fully extended eicosyl group, said R¹defining a three-dimensional volume, when rotated about an axis drawnthrough the SO₂-bonded 1-position and the 4-position of a 6-memberedring radical or drawn through the SO₂-bonded 1-position and the centerof 3,4-bond of a 5-membered ring radical, whose widest dimension in adirection transverse to the axis of rotation is about that of onefuranyl ring to about that of two phenyl rings;

[0042] R² and R³ are independently hydrido, C₁-C₄ hydrocarbyl, hydroxylor amino, or R² and R³ together with the depicted carbon atom to whichthey are bonded form a 6-membered heterocyclic ring in which theheteroatom is oxygen, sulfur or nitrogen, said heteroatom beingoptionally substituted with one or two oxygens when sulfur and beingoptionally substituted with a moiety selected from the group consistingof a C₁-C₄ hydrocarbyl, C₃-C₆ cyclohydrocarbyl, C₁-C₄ acylhydrocarbyl,and sulfonyl C₁-C₄ hydrocarbyl group when nitrogen.

[0043] In the above structural formula and other formulas herein, one ofy and z is one and the other is zero so that the sum of y plus z is one.Thus, either the —CR²R³— or the —CH₂— group of such formulas is absentin each contemplated compound.

[0044] The ring structure W is a 5- or 6-membered divalent aromatic orheteroaromatic ring in which the depicted —CR²R³— and —CH₂— groups arebonded to adjacent carbon atoms of the aryl or heteroaryl ring. As aconsequence, the hydroxamate carbonyl group and the R¹-linked sulfonylgroup are separated by three carbon atoms in each contemplated compound.

[0045] Contemplated divalent aromatic or heteroaromatic rings include1,2-phenylene, 2,3-pyridinylene, 3,4-pyridinylene, 4,5-pyridinylene,2,3-pyrazinylene, 4,5-pyrimidinylene, and 5,6-pyrimidinylene groups.1,2-Phenylene is a particularly preferred divalent aromatic orheteroaromatic ring, and is used illustratively herein as W.

[0046] As noted above, an R¹ substituent contains a 5- or 6-memberedcyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bondeddirectly to the depicted SO₂-group. An R¹ substituent also has length,width and substitution requirements that are discussed in detail below.It is noted here, however, that a single- ringed or fused ringcyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is not itselflong enough to fulfill the length requirement. As such, thatcyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical must itself besubstituted.

[0047] Exemplary 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl orheteroaryl radicals that can constitute a portion of a R¹ substituentand are themselves substituted as discussed herein include phenyl, 2-,3-, or 4-pyridyl, 2-naththyl, 2-pyrazinyl, 2- or 5-pyrimidinyl, 2- or3-benzo(b)thienyl, 8-purinyl, 2- or 3-furyl, 2- or 3-pyrrolyl,2-imidazolyl, cyclopentyl, cyclohexyl, 2- or 3-piperidinyl, 2- or3-morpholinyl, 2- or 3-tetrahydropyranyl, 2-imidazolidinyl, 2- or3-pyrazolidinyl and the like. A phenyl radical is particularly preferredand is used illustratively herein.

[0048] When examined along its longest chain of atoms, an R¹substituent, including its own substituent when present, has a totallength equivalent to a length that is greater than that of a fullyextended saturated chain of six carbon atoms (a hexyl group); i.e., alength of a heptyl chain or longer, and a length that is less than thatof a fully extended saturated chain of about 20 carbons (an eicosylgroup). Preferably, that length is about 8 to about 18 carbon atoms,even though many more atoms may be present in ring structures orsubstituents. This length requirement is discussed further below.

[0049] Looked at more generally, and aside from specific moieties fromwhich it is constructed, an R¹ substituent (radical, group or moiety)has a length of a heptyl group or greater. Such an R¹ substituent alsohas a length that is less than that of an eicosyl group. That is to saythat a R¹ is a substituent having a length greater than that of a fullyextended saturated six carbon chain and shorter than that of a fullyextended saturated twenty carbon chain, and more preferably, a lengthgreater than that of a octyl group and less than that of a palmitylgroup. The radical chain lengths are measured along the longest linearatom chain in the radical, following the skeletal atoms of a ring wherenecessary. Each atom in the chain, e.g. carbon, oxygen or nitrogen, ispresumed to be carbon for ease in calculation.

[0050] Such lengths can be readily determined by using published bondangles, bond lengths and atomic radii, as needed, to draw and measure achain, or by building models using commercially available kits whosebond angles, lengths and atomic radii are in accord with accepted,published values. Radical (substituent) lengths can also be determinedsomewhat less exactly by presuming, as is done here, that all atoms havebond lengths of saturated carbon, that unsaturated and aromatic bondshave the same lengths as saturated bonds and that bond angles forunsaturated bonds are the same as those for saturated bonds, althoughthe above-mentioned modes of measurement are preferred. For example, a4-phenyl or 4-pyridyl group has a length of a four carbon chain, as doesa propoxy group, whereas a biphenyl group has a length of about an eightcarbon chain using a contemplated measurement mode.

[0051] In addition, an R¹ substituent, when rotated about an axis drawnthrough the SO₂-bonded 1-position and the 4-position of a 6-memberedring radical or the SO₂-bonded 1-position and through the 3,4 bond of a5-membered ring radical defines a three-dimensional volume whose widestdimension has the width of about one furanyl ring to about the width oftwo phenyl rings in a direction transverse to that axis to rotation.

[0052] When utilizing this width or volume criterion, a fused ringsystem such as a naphthyl or purinyl radical is considered to be a 6- or5-membered ring that is substituted at appropriate positions numberedfrom the SO₂-linkage that is deemed to be at the 1-position as discussedbefore. Thus, a 2-naphthyl substituent or an 8-purinyl substituent is anappropriately sized R¹ radical as to width when examined using the aboverotational width criterion. On the other hand, a 1-naphthyl group or a7- or 9-purinyl group is too large upon rotation and is excluded.

[0053] As a consequence of these length and width requirements, R¹substituents such as 4-(phenyl)phenyl [biphenyl],4-(4′-methoxyphenyl)phenyl, 4-(phenoxy)phenyl, 4-(thiophenyl)phenyl[4-(phenylthio)phenyl], 4-(phenylazo)phenyl 4-(phenylureido)phenyl,4-(anilino)phenyl, 4-(nicotinamido)phenyl, 4-(isonicotinamido)phenyl,4-(picolinamido)phenyl and 4-(benzamido)phenyl are among particularlypreferred R¹ substituents, with 4-(phenoxy)phenyl and4-(thiophenyl)phenyl being most preferred.

[0054] An SO₂-linked cyclohydrocarbyl, heterocyclo, aryl or heteroarylradical is a 5- or 6-membered single-ring that is itself substitutedwith one other substituent, R⁴. The SO₂-linked single-ringedcyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical isR⁴-substituted at its own 4-position when a 6-membered ring and at itsown 3-position when a 5-membered ring. The cyclohydrocarbyl,heterocyclo, aryl or heteroaryl radical to which R⁴ is bonded ispreferably a phenyl group, so that R¹ is preferably PhR⁴ in which R⁴ isbonded at the 4-position of the SO₂-linked phenyl (Ph) radical, and inwhich R⁴ can itself be optionally substituted as is discussedhereinafter. Substitution at the 2-position of a SO₂-linkedcyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical appears togreatly lessen inhibitory potency toward MMP enzymes, and is absent froma contemplated compound.

[0055] A contemplated R⁴ substituent can be a single-ringedcyclohydrocarbyl, heterocyclo, aryl or heteroaryl group or anothersubstituent having a chain length of 3 to about 14 carbon atoms such asa hydrocarbyl or hydrocarbyloxy group [e.g., C₃-C₁₄ hydrocarbyl orO—C₂-C₁₄ hydrocarbyl], a phenyl group, a phenoxy group [—OC₆H₅], athiophenoxy group [phenylsulfanyl; —SC₆H₅], an anilino group [—NHC₆H₅],a phenylazo group [—N₂C₆H₅], a phenylureido group [anilinecarbonylamino; —NHC(O)NH—C₆H₅], a benzamido group [—NHC(O)C₆H₅], anicotinamido group [3-NHC(O)C₅H₄N], an isonicotinamido group[4-NHC(O)C₅H₄N], or a picolinamido group [2-NHC(O)C₅H₄N]. As notedbefore in conjunction with the discussion of R¹, most preferred R⁴substituents are phenoxy and thiophenoxy groups that are preferablythemselves free of substitution. Additionally contemplated R⁴substituent groups include a heterocyclo, heterocyclohydrocarbyl,arylhydrocarbyl, arylheterocyclohydrocarbyl, heteroarylhydrocarbyl,heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl,aryloxyhydrocarbyl, hydrocarboylhydrocarbyl,arylhydrocarboylhydrocarbyl, arylcarbonylhydrocarbyl, arylazoaryl,arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, hydrocarbylthioaryl,arylthiohydrocarbyl, heteroarylthiohydrocarbyl,hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl,arylhydrocarbylthioaryl, arylhydrocarbylamino,heteroarylhydrocarbylamino, or a heteroarylthio group.

[0056] A contemplated R⁴ substituent can itself also be substituted withone or more substituent radicals at the meta- or para-position or bothof a six-membered ring with a single atom or a substituent containing alongest chain of up to ten atoms, excluding hydrogen. Exemplarysubstituent radicals include a halo, hydrocarbyl, hydrocarbyloxy, nitro,cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy,mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino,arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino,heteroarhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy,hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino,cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino,heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio,heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio,arylhydrocarbylamino, heterocyclic, heteroaryl,hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl,arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhydrocarboyloxy,hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio,hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl,hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl,hydrocarbylhydroxycarbonylhydrocarbylthio,hydrocarbyloxycarbonylhydrocarbyloxy,hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino,arylcarbonylamino, cyclohydrocarbylcarbonylamino,heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino,heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino,heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino,arylhydrocarbylsulfonylamino, heteroarylsulfonylamino,heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino,heterocyclohydrocarbylsulfonylamino and N-monosubstituted orN,N-disubstituted aminohydrocarbyl group wherein the substituent(s) onthe nitrogen are selected from the group consisting of hydrocarbyl,aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl,hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the nitrogen andtwo substituents attached thereto form a 5- to 8-membered heterocyclicor heteroaryl ring group.

[0057] Thus, initial studies indicate that so long as the length,substitution and width (volume upon rotation) requirements of anSO₂-linked R¹ substituent discussed herein are met, an R¹ substituentcan be extremely varied.

[0058] A particularly preferred R⁴ substituent of an SO₂-linked Ph groupis a single-ringed aryl or heteroaryl, phenoxy, thiophenoxy, phenylazo,phenylureido, nicotinamido, isonicotinamido, picolinamido, anilino orbenzamido group that is unsubstituted or is itself substituted(optionally substituted) at the para-position when a 6-membered ring orthe 3-position when a 5-membered ring. Here, single atoms such ashalogen moieties or substituents that contain one to a chain of aboutten atoms other than hydrogen such as C₁-C₁₀ hydrocarbyl, C₁-C₉hydrocarbyloxy or carboxyethyl groups can be used.

[0059] Exemplary particularly preferred PhR⁴ (particularly preferred R¹)substituents include biphenyl, 4-phenoxyphenyl, 4-thiophenoxyphenyl,4-benzamidophenyl, 4-phenylureido, 4-anilinophenyl, 4-nicotinamido,4-isonicotinamido, and 4-picolinamido. Exemplary particularly preferredR⁴ groups contain a 6-membered aromatic ring and include a phenyl group,a phenoxy group, a thiophenoxy group, a phenylazo group, a phenylureidogroup, an anilino group, a nicotinamido group, an isonicotinamido group,a picolinamido group and a benzamido group.

[0060] More specifically, a particularly preferred sulfonylbutanhydroxamate compounds has an R⁴ substituent that is a phenyl group,a phenoxy group, a thiophenoxy group, a phenylazo group, a phenylureidogroup, an anilino group, a nicotinamido group, an isonicotinamido group,a picolinamido group or a benzamido group that is itself optionallysubstituted at its own meta or para-position or both with a moiety thatis selected from the group consisting of a halogen, a C₁-C₉hydrocarbyloxy (—O—C₁-C₉ hydrocarbyl) group, a C₁-C₁₀ hydrocarbyl group,a di-C₁-C₉ hydrocarbylamino [—N(C₁-C₉ hydrocarbyl)(C₁-C₉ hydrocarbyl)]group, a carboxyl C₁-C₈ hydrocarbyl (C₁-C₈ hydrocarbyl-CO₂H) group, aC₁-C₄ hydrocarbyloxy carbonyl C₁-C₄ hydrocarbyl [C₁-C₄hydrocarbyl-O-(CO)-C₁-C₄ hydrocarbyl] group, a C₁-C₄hydrocarbyloxycarbonyl C₁-C₄ hydrocarbyl [C₁-C₄ hydrocarbyl(CO)-O-C₁-C₄hydrocarbyl] group and a C₁-C₈ hydrocarbyl carboxamido [—NH(CO)—C₁-C₈hydrocarbyl] group, or is substituted at the meta- and para-positions bytwo methyl groups or by a C₁-C₂ alkylenedioxy group such as amethylenedioxy group.

[0061] Inasmuch as a contemplated SO₂-linked cyclohydrocarbyl,heterocyclo, aryl or heteroaryl radical is itself preferably substitutedwith a 6-membered aromatic ring, two nomenclature systems are usedtogether herein for ease in understanding substituent positions. Thefirst system uses position numbers for the ring directly bonded to theSO₂-group, whereas the second system uses ortho, meta or para for theposition of one or more substituents of a 6-membered ring bonded to aSO₂-linked cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical.When a R⁴ substituent is other than a 6-membered ring, substituentpositions are numbered from the position of linkage to the aromatic orheteroaromatic ring. Formal chemical nomenclature is used in namingparticular compounds.

[0062] Thus, the 1-position of an above-discussed SO₂-linkedcyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is theposition at which the SO₂-group is bonded to the ring. The 4- and3-positions of rings discussed here are numbered from the sites ofsubstituent bonding from the SO₂-linkage as compared to formalized ringnumbering positions used in heteroaryl nomenclature.

[0063] In preferred embodiments, a contemplated compound corresponds instructure to Formula IA, wherein W. X, y, z, R² and R³ are as definedabove, Ph is phenyl substituted at the 4-position with substituent R⁴that is defined hereinabove.

[0064] R² and R³ substituents are independently selected.

[0065] Those groups can be hydrido, C₁-C₄ hydrocarbyl such as methyl,ethyl, propyl, allyl, propargyl, butyl and but-2-ynyl and the like,hydroxyl or amino.

[0066] In addition, R² and R³ together with the depicted carbon atom towhich they are bonded can form a 6-membered heterocyclic ring in whichthe heteroatom is oxygen, sulfur or nitrogen. That heteroatom isoptionally substituted with one or two oxygens when sulfur, and whennitrogen is optionally substituted with a moiety (R⁵) selected from thegroup consisting of a C₁-C₄ hydrocarbyl (as above), C₃-C₆cyclohydrocarbyl such as cyclopropyl, cyclobutyl, cyclopentenyl andcyclohexenyl, C₁-C₄ acylhydrocarbyl such as formyl, acetyl, acrylyol,and butyryl, and a sulfonyl C₁-C₄ hydrocarbyl group such asmethylsulfonyl, ethylsulfonyl and the like. Thus, R² and R³ together canform a 4-tetrahydrothiopyranyl group, its corresponding sulfoxide orsulfone, a 4-piperidinyl or a 4-tetrahydropyranyl group. When present,the 4-piperidinyl group can be N-substituted with an above-described R⁵substituent.

[0067] The length of a R¹ substituent bonded to the SO₂ group isbelieved to play a role in the overall activity of a contemplatedinhibitor compound against MMP enzymes generally. Thus, a compoundhaving an R¹ substituent that is shorter in length than a heptyl group,e.g., a 4-methoxyphenyl group (compound of Example 6), typicallyexhibits moderate to poor inhibitory activity against all of the MMPenzymes, whereas compounds whose R¹ substituents have a length of aboutan heptyl chain or longer, e.g., a 4-phenoxyphenyl group (compound ofExample 1) that has a length of about a nine-carbon chain, typicallyexhibit good to excellent potencies against MMP-13 or MMP-2 and alsoselectivity against MMP-1. Exemplary data are provided in Table 32hereinafter in which the activities of the above two compounds can becompared.

[0068] The data of Table 32 also illustrate that compounds of seeminglysimilar structure are not particularly effective inhibitors of theactivity of MMP-13. Thus, those data indicate that the before-notedspacing of three carbon atoms between the carbonyl of the hydroxamateand the sulfonyl group has some criticality for these compounds and thatthe third carbon cannot be replaced by an amido nitrogen atom.

[0069] In view of the above-discussed preferences, compoundscorresponding in structure to particular formulas constituteparticularly preferred embodiments.

[0070] In one of those embodiments, a contemplated compound correspondsin structure to Formula II, below,

[0071] wherein W, R¹, R², and R³ are as defined above, and R¹ ispreferably PhR⁴, as is also defined above.

[0072] In another of those embodiments, a contemplated compoundcorresponds in structure to Formula III, below,

[0073] wherein W, R¹, R², and R³ are as defined above, and R¹ ispreferably PhR⁴, as is also defined above.

[0074] Taking into account the before-stated preference that W be a1,2-phenylene radical and the preference for R¹ being PhR⁴, particularlypreferred compounds of Formulas II and III correspond in structure toFormulas IA and IIIA, below,

[0075] wherein the above definitions for R², R³ and PhR⁴ also apply.

[0076] In yet another group of preferred compounds, R² and R³ togetherwith the carbon atom to which they are bonded form a 4-piperidinyl ortetrahydropyranyl group in which the nitrogen of the 4-piperidinyl groupis optionally substituted with a moiety R⁵ selected from the groupconsisting of a C₁-C₄ hydrocarbyl, C₃-C₆ cyclohydrocarbyl, C₁-C₄acylhydrocarbyl, and a sulfonyl C₁-C₄ hydrocarbyl group. Those preferredcompounds correspond in structure to Formulas V and IV, respectively,

[0077] wherein R¹ is as defined above, and is preferably PhR⁴, as isalso defined above.

[0078] Again taking into account the before-stated preference that W bea 1,2-phenylene radical and the preference for R¹ being PhR⁴,particularly preferred compounds of Formulas IV and V correspond instructure to Formulas IVA and VA, below, wherein the above definitionsfor R⁵ and PhR⁴ also apply.

[0079] The word “hydrocarbyl” is used herein as a short hand term toinclude straight and branched chain aliphatic as well as alicyclicgroups or radicals that contain only carbon and hydrogen. Thus, alkyl,alkenyl and alkynyl groups are contemplated, whereas aromatichydrocarbons such as phenyl and naphthyl groups, which strictly speakingare also hydrocarbyl groups, are referred to herein as aryl groups orradicals, as discussed hereinafter. Where a specific aliphatichydrocarbyl substituent group is intended, that group is recited; i.e.,C₁-C₄ alkyl, methyl or dodecenyl. Exemplary hydrocarbyl groups contain achain of 1 to about 12 carbon atoms, and preferably one to about 10carbon atoms.

[0080] A particularly preferred hydrocarbyl group is an alkyl group. Asa consequence, a generalized, but more preferred substituent can berecited by replacing the descriptor “hydrocarbyl” with “alkyl” in any ofthe substituent groups enumerated herein.

[0081] Examples of alkyl radicals include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl,hexyl, octyl and the like. Examples of suitable alkenyl radicals includeethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl,1,4-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, decenyl and the like.Examples of alkynyl radicals include ethynyl, 2-propynyl, 3-propynyl,decynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.

[0082] Usual chemical suffix nomenclature is followed when using theword “hydrocarbyl” except that the usual practice of removing theterminal “yl” and adding an appropriate suffix is not always followedbecause of the possible similarity of a resulting name to one or moresubstituents. Thus, a hydrocarbyl ether is referred to as a“hydrocarbyloxy” group rather than a “hydrocarboxy” group as maypossibly be more proper when following the usual rules of chemicalnomenclature. On the other hand, a hydrocarbyl group containing a—C(O)O— functionality is referred to as a hydrocarboyl group inasmuch asthere is no ambiguity in using that suffix. As a skilled worker willunderstand, a substituent that cannot exist such as a C₁ alkenyl groupis not intended to be encompassed by the word “hydrocarbyl”.

[0083] The term “carbonyl”, alone or in combination, means a —C(═O)—group wherein the remaining two bonds (valences) are independentlysubstituted. The term “thiol” or “sulfhydryl”, alone or in combination,means a —SH group. The term “thio” or “thia”, alone or in combination,means a thiaether group; i.e., an ether group wherein the ether oxygenis replaced by a sulfur atom.

[0084] The term “amino”, alone or in combination, means an amine or —NH₂group, whereas the term mono-substituted amino, alone or in combination,means a substituted amine —N(H) (substituent) group wherein one hydrogenatom is replaced with a substituent, and disubstituted amine means a—N(substituent)₂ wherein two hydrogen atoms of the amino group arereplaced with independently selected substituent groups. Amines, aminogroups and amides are classes that can be designated as primary (I°),secondary (II°) or tertiary (III°) or unsubstituted, mono-substituted ordi-substituted depending on the degree of substitution of the aminonitrogen. Quaternary amine (IV°) means a nitrogen with four substituents(—N⁺(substituent)₄) that is positively charged and accompanied by acounter ion or N-oxide means one substituent is oxygen and the group isrepresented as (—N⁺(substituent)₃—O^(—)); i.e., the charges areinternally compensated.

[0085] The term “cyano”, alone or in combination, means a —C-triplebond-N (—CN) group. The term “azido”, alone or in combination, means an—N-double bond-N-double bond-N— (—N═N═N—).

[0086] The term “hydroxyl”, alone or in combination, means a —OH group.The term “nitro”, alone or in combination, means a —NO₂ group.

[0087] The term “azo”, alone or in combination, means a —N═N— groupwherein the bonds at the terminal positions are independentlysubstituted. The term “hydrazino”, alone or in combination, means a—NH—NH— group wherein the remaining two bonds (valences) areindependently substituted. The hydrogen atoms of the hydrazino group canbe replaced, independently, with substituents and the nitrogen atoms canform acid addition salts or be quaternized.

[0088] The term “sulfonyl”, alone or in combination, means a —S(O)₂—group wherein the remaining two bonds (valences) can be independentlysubstituted. The term “sulfoxido”, alone or in combination, means a—S(═O)₁— group wherein the remaining two bonds (valences) can beindependently substituted. The term “sulfonylamide”, alone or incombination, means a —S(═O)₂—N═ group wherein the remaining three bonds(valences) are independently substituted. The term “sulfinamido”, aloneor in combination, means a —S(═O)₁N═ group wherein the remaining threebonds (valences) are independently substituted. The term “sulfenamide”,alone or in combination, means a —S—N═ group wherein the remaining threebonds (valences) are independently substituted.

[0089] The term “hydrocarbyloxy”, alone or in combination, means anhydrocarbyl ether radical wherein the term hydrocarbyl is as definedabove. Examples of suitable hydrocarbyl ether radicals include methoxy,ethoxy, n-propoxy, isopropoxy, allyloxy, n-butoxy, iso-butoxy,sec-butoxy, tert-butoxy and the like. The term “cyclohydrocarbyl”, aloneor in combination, means a hydrocarbyl radical that contains 3 to about8 carbon atoms, preferably from about 3 to about 6 carbon atoms, and iscyclic. The term “cyclohydrocarbylhydrocarbyl” means an hydrocarbylradical as defined above which is substituted by a cyclohydrocarbyl asalso defined above. Examples of such cyclohydrocarbylhydrocarbylradicals include cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexylcyclooctynyl and the like.

[0090] The term “aryl”, alone or in combination, means a phenyl ornaphthyl radical that optionally carries one or more substituentsselected from hydrocarbyl, hydrocarbyloxy, halogen, hydroxy, amino,nitro and the like, such as phenyl, p-tolyl, 4-methoxyphenyl,4-(tert-butoxy)phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl,and the like. The term “arylhydrocarbyl”, alone or in combination, meansan hydrocarbyl radical as defined above in which one hydrogen atom isreplaced by an aryl radical as defined above, such as benzyl,2-phenylethyl and the like. The term “arylhydrocarbyloxycarbonyl”, aloneor in combination, means a radical of the formula —C(O)—O—arylhydrocarbyl in which the term “arylhydrocarbyl” has the significancegiven above. An example of an arylhydrocarbyloxycarbonyl radical isbenzyloxycarbonyl. The term “aryloxy” means a radical of the formulaaryl-O— in which the term aryl has the significance given above. Theterm “aromatic ring” in combinations such as substituted-aromatic ringsulfonamide, substituted-aromatic ring sulfinamide orsubstituted-aromatic ring sulfenamide means aryl or heteroaryl asdefined above.

[0091] The terms “hydrocarbyloyl” or “hydrocarbylcarbonyl”, alone or incombination, mean an acyl radical derived from an hydrocarbylcarboxylicacid, examples of which include acetyl, propionyl, acryloyl, butyryl,valeryl, 4-methylvaleryl, and the like. The term“cyclohydrocarbylcarbonyl” means an acyl group derived from a monocyclicor bridged cyclohydrocarbylcarboxylic acid such as cyclopropanecarbonyl,cyclohexenecarbonyl, adamantanecarbonyl, and the like, or from abenz-fused monocyclic cyclohydrocarbylcarboxylic acid that is optionallysubstituted by, for example, a hydrocarbyloylamino group, such as1,2,3,4-tetrahydro-2-naphthoyl,2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl. The terms“arylhydrocarbyloyl” or “arylhydrocarbylcarbonyl” mean an acyl radicalderived from an aryl-substituted hydrocarbylcarboxylic acid such asphenylacetyl, 3-phenylpropenyl (cinnamoyl), 4-phenylbutyryl,(2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, 4-aminocinnamoyl,4-methoxycinnamoyl and the like.

[0092] The terms “aroyl” or “arylcarbonyl” means an acyl radical derivedfrom an aromatic carboxylic acid. Examples of such radicals includearomatic carboxylic acids, an optionally substituted benzoic ornaphthoic acid such as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl,4-(benzyloxycarbonyl)benzoyl, 2-naphthoyl, 6-carboxy-2 naphthoyl,6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl,3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the like.

[0093] The heterocyclyl (heterocyclo) or heterocyclohydrocarbyl portionof a heterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylhydrocarbyloxycarbonyl, or heterocyclohydrocarbyl group orthe like is a saturated or partially unsaturated monocyclic, bicyclic ortricyclic heterocycle that contains one to four hetero atoms selectedfrom nitrogen, oxygen and sulphur, which is optionally substituted onone or more carbon atoms by a halogen, alkyl, alkoxy, oxo group, and thelike, and/or on a secondary nitrogen atom (i.e., —NH—) by anhydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloyl, aryl orarylhydrocarbyl or on a tertiary nitrogen atom (i.e. ═N—) by oxido andthat is attached via a carbon atom. The tertiary nitrogen atom withthree substituents can also form a N-oxide [═N(O)—] group. Examples ofsuch heterocyclyl groups are pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiamorpholinyl, and the like.

[0094] The heteroaryl portion of a heteroaroyl, heteroaryloxycarbonyl,or a heteroarylhydrocarbyloyl (heteroarylhydrocarbyl carbonyl) group orthe like is an aromatic monocyclic, bicyclic, or tricyclic heterocyclethat contains the hetero atoms and is optionally substituted as definedabove with respect to the definition of heterocyclyl. A “heteroaryl”group is an aromatic heterocyclic ring substituent that can contain one,two, three or four atoms in the ring that are other than carbon. Thoseheteroatoms can be nitrogen, sulfur or oxygen. A heteroaryl group cancontain a single five- or 6-membered ring or a fused ring system thatcontains two 6-membered rings or a five- and a 6-membered ring.Exemplary heteroaryl groups include 6-membered ring substituents such aspyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ringsubstituents such as 1,3,5-, 1,2,4- or 1,2,3-triazinyl, imidazyl,furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-,1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl groups;six/5-membered fused ring substituents such as benzothiofuranyl,isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl andanthranilyl groups; and six/6-membered fused rings such as 1,2-, .1,4-,.2,3- and 2,1-benzopyronyl, quinolinyl, isoquinolinyl, cinnolinyl,quinazolinyl, and 1,4-benzoxazinyl groups.

[0095] The term “cyclohydrocarbylhydrocarbyloxycarbonyl” means an acylgroup derived from a cyclohydrocarbylhydrocarbyloxycarboxylic acid ofthe formula cyclohydrocarbylhydrocarbyl-O-COOH whereincyclohydrocarbylhydrocarbylhas the significance given above. The term“aryloxyhydrocarbyloyl” means an acyl radical of the formulaaryl-O-hydrocarbyloyl wherein aryl and hydrocarbyloyl have thesignificance given above. The term “heterocyclyloxycarbonyl” means anacyl group derived from heterocyclyl-O-COOH wherein heterocyclyl is asdefined above. The term “heterocyclylhydrocarbyloyl” is an acyl radicalderived from a heterocyclyl-substituted hydrocarbylcarboxylic acidwherein heterocyclyl has the significance given above. The term“heterocyclylhydrocarbyloxycarbonyl” means an acyl radical derived froma heterocyclyl-substituted hydrocarbyl-O-COOH wherein heterocyclyl hasthe significance given above. The term “heteroaryloxycarbonyl”, means anacyl radical derived from a carboxylic acid represented byheteroaryl-O-COOH wherein heteroaryl has the significance given above.

[0096] The term “aminocarbonyl” alone or in combination, means anamino-substituted carbonyl (carbamoyl) group derived from anamino-substituted carboxylic acid wherein the amino group can be aprimary, secondary or tertiary amino group containing substituentsselected from hydrogen, hydrocarbyl, aryl, aralkyl, cyclohydrocarbyl,cyclohydrocarbylhydrocarbyl radicals and the like. The term“aminohydrocarbyloyl” means an acyl group derived from anamino-substituted hydrocarbylcarboxylic acid wherein the amino group canbe a primary, secondary or tertiary amino group containing substituentsindependently selected from hydrogen, alkyl, aryl, aralkyl,cyclohydrocarbyl, cyclohydrocarbylhydrocarbyl radicals and the like.

[0097] The term “halogen” means fluorine, chlorine, bromine or iodine.The term “halohydrocarbyl” means a hydrocarbyl radical having thesignificance as defined above wherein one or more hydrogens are replacedwith a halogen. Examples of such halohydrocarbyl radicals includechloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl,trifluoromethyl, 1,1,1-trifluoroethyl and the like. The termperfluorohydrocarbyl means a hydrocarbyl group wherein each hydrogen hasbeen replaced by a fluorine atom. Examples of such perfluorohydrocarbylgroups, in addition to trifluoromethyl above, are perfluorobutyl,perfluoroisopropyl, perfluorododecyl and perfluorodecyl.

[0098] Table 1 through Table 31, below, show several contemplatedsulfonyl divalent aryl or heteroaryl hydroxamic acid compounds asstructural formulas that illustrate substituent groups. Each group ofcompounds is illustrated by a generic formula, followed by a series ofpreferred moieties or groups that constitute various substituents thatcan be attached at the position clearly shown in the generic structure.The substituent symbols, e.g., R¹, R² X, are as shown in each Table, andare different from those shown elsewhere herein in structural formulasbearing Roman numerals. One or two bonds (straight lines) are shown withthose substituents to indicate the respective positions of attachment inthe illustrated compound. This system is well known in the chemicalcommunication arts and is widely used in scientific papers andpresentations. TABLE 1

Example R¹ R² 1 —H —H 2 —H —CH₃ 3 —CH₃ —CH₃ 4 —H —OH 5 —CH₃ —OH 6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

[0099] TABLE 2

Example R¹ R² 1 —H —H 2 —H —CH₃ 3 —CH₃ —CH₃ 4 —H —OH 5 —CH₃ —OH 6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

[0100] TABLE 3

Example R¹ R² X Ar 1

O

2

O

3

O

4

O

5

O

6

O

7

O

8

O

9

S

10

S

[0101] TABLE 4

Example X Ar 1 O

2 O

3 O

4 O

5 O

6 O

7 O

8 O

9 O

10 O

11 O

12 S

13 S

14 S

15 S

16 S

17 S

18 S

19 S

20 S

21 S

22 S

[0102] TABLE 5

Example X Ar 1 O

2 O

3 O

4 O

5 O

6 O

7 O

8 O

9 O

10 O

11 O

12 S

13 S

14 S

15 S

16 S

17 S

18 S

19 S

20 S

21 S

22 S

[0103] TABLE 6

Example X Ar 1 O

2 O

3 O

4 O

5 O

6 O

7 O

8 O

9 S

10 S

11 S

12 S

13 S

14 S

15 S

16 S

[0104] TABLE 7

Example X 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

[0105] TABLE 8

Example X 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

[0106] TABLE 9

Example X 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

[0107] TABLE 10

Example X 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

[0108] TABLE 11

Example X 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

[0109] TABLE 12

Example X 1

2

3

4

5

6

7

8

9

10

11

[0110] TABLE 13

[0111] TABLE 14

[0112] TABLE 15

[0113] TABLE 16

[0114] TABLE 17

Example X Ar 1 O

2 O

3 O

4 O

5 O

6 O

7 O

8 O

9 O

10 O

11 O

12 S

13 S

14 S

15 S

16 S

17 S

18 S

19 S

20 S

21 S

22 S

[0115] TABLE 18

Example X 1

2

3

4

5

6

7

8

9

10

11

[0116] TABLE 19

Example X 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

[0117] TABLE 20

Example X 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

[0118] TABLE 21

Example X Ar 1 O

2 O

3 O

4 O

5 O

6 O

7 O

8 O

9 S

10 S

11 S

12 S

13 S

14 S

15 S

16 S

[0119] TABLE 22

[0120] TABLE 23

[0121] TABLE 24

[0122] TABLE 25

[0123] TABLE 26

[0124] TABLE 27

[0125] TABLE 28

[0126] TABLE 29

Example X Ar 1 O

2 O

3 S

4 S

5 S

6 S

[0127] TABLE 30

Example R¹ R² X Ar 1

O

2

O

3

O

4

O

5

O

6

O

7

O

8

O

9

S

10

S

11

S

[0128] TABLE 31

Example X Ar 1 O

2 O

3 S

4 S

5 S

[0129] Treatment Process

[0130] A process for treating a host mammal having a conditionassociated with pathological matrix metalloprotease activity is alsocontemplated. That process comprises administering a compound describedhereinbefore in an MMP enzyme-inhibiting effective amount to a mammalianhost having such a condition. The use of administration repeated aplurality of times is particularly contemplated.

[0131] A contemplated compound is used for treating a host mammal suchas a mouse, rat, rabbit, dog, horse, primate such as a monkey,chimpanzee or human that has a condition associated with pathologicalmatrix metalloprotease activity.

[0132] Also contemplated is the similar use of a contemplated compoundin the treatment of a disease state that can be affected by the activityof metalloproteases such as TNF-α convertase. Exemplary of such diseasestates are the acute phase responses of shock and sepsis, coagulationresponses, hemorrhage and cardiovascular effects, fever andinflammation, anorexia and cachexia.

[0133] In treating a disease condition associated with pathologicalmatrix metalloproteinase activity, a contemplated MMP inhibitor compoundcan be used, where appropriate, in the form of an amine salt derivedfrom an inorganic or organic acid. Exemplary acid salts include but arenot limited to the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate andundecanoate.

[0134] Also, a basic nitrogen-containing group can be quaternized withsuch agents as lower alkyl (C₁-C₆) halides, such as methyl, ethyl,propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates likedimethyl, diethyl, dibuytl, and diamyl sulfates, long chain (C₈-C₂₀)halides such as decyl, lauryl, myristyl and dodecyl chlorides, bromidesand iodides, aralkyl halides like benzyl and phenethyl bromides, andothers to provide enhanced water-solubility. Water or oil-soluble ordispersible products are thereby obtained as desired. The salts areformed by combining the basic compounds with the desired acid.

[0135] Other compounds useful in this invention that are acids can alsoform salts. Examples include salts with alkali metals or alkaline earthmetals, such as sodium, potassium, calcium or magnesium or with organicbases or basic quaternary ammonium salts.

[0136] In some cases, the salts can also be used as an aid in theisolation, purification or resolution of the compounds of thisinvention.

[0137] Total daily dose administered to a host mammal in single ordivided doses of an MMP enzyme-inhibiting effective amount can be inamounts, for example, of about 0.001 to about 100 mg/kg body weightdaily, preferably about 0.001 to about 30 mg/kg body weight daily andmore usually about 0.01 to about 10 mg. Dosage unit compositions cancontain such amounts or submultiples thereof to make up the daily dose.A suitable dose can be administered, in multiple sub-doses per day.Multiple doses per day can also increase the total daily dose, shouldsuch dosing be desired by the person prescribing the drug.

[0138] The dosage regimen for treating a disease condition with acompound and/or composition of this invention is selected in accordancewith a variety of factors, including the type, age, weight, sex, dietand medical condition of the patient, the severity of the disease, theroute of administration, pharmacological considerations such as theactivity, efficacy, pharmacokinetic and toxicology profiles of theparticular compound employed, whether a drug delivery system is utilizedand whether the compound is administered as part of a drug combination.Thus, the dosage regimen actually employed can vary widely and thereforecan deviate from the preferred dosage regimen set forth above.

[0139] A compound useful in the present invention can be formulated as apharmaceutical composition. Such a composition can then be administeredorally, parenterally, by inhalation spray, rectally, or topically indosage unit formulations containing conventional nontoxicpharmaceutically acceptable carriers, adjuvants, and vehicles asdesired. Topical administration can also involve the use of transdermaladministration such as transdermal patches or iontophoresis devices. Theterm parenteral as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection, or infusiontechniques. Formulation of drugs is discussed in, for example, Hoover,John E., Remington's Pharmaceutical Sciences, Mack Publishing Co.,Easton, Pa.; 1975 and Liberman, H. A. and Lachman, L., Eds.,Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980.

[0140] Injectable preparations, for example, sterile injectable aqueousor oleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that can be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables. Dimethyl acetamide, surfactantsincluding ionic and non-ionic detergents, polyethylene glycols can beused. Mixtures of solvents and wetting agents such as those discussedabove are also useful.

[0141] Suppositories for rectal administration of the drug can beprepared by mixing the drug with a suitable nonirritating excipient suchas cocoa butter, synthetic mono- di- or triglycerides, fatty acids andpolyethylene glycols that are sold at ordinary temperatures but liquidat the rectal temperature and will therefore melt in the rectum andrelease the drug.

[0142] Solid dosage forms for oral administration can include capsules,tablets, pills, powders, and granules. In such solid dosage forms, thecompounds of this invention are ordinarily combined with one or moreadjuvants appropriate to the indicated route of administration. Ifadministered per os, the compounds can be admixed with lactose, sucrose,starch powder, cellulose esters of alkanoic acids, cellulose alkylesters, talc, stearic acid, magnesium stearate, magnesium oxide, sodiumand calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum,sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, andthen tableted or encapsulated for convenient administration. Suchcapsules or tablets can contain a controlled-release formulation as canbe provided in a dispersion of active compound in hydroxypropylmethylcellulose. In the case of capsules, tablets, and pills, the dosage formscan also comprise buffering agents such as sodium citrate, magnesium orcalcium carbonate or bicarbonate. Tablets and pills can additionally beprepared with enteric coatings.

[0143] For therapeutic purposes, formulations for parenteraladministration can be in the form of aqueous or non-aqueous isotonicsterile injection solutions or suspensions. These solutions andsuspensions can be prepared from sterile powders or granules having oneor more of the carriers or diluents mentioned for use in theformulations for oral administration. The compounds can be dissolved inwater, polyethylene glycol, propylene glycol, ethanol, corn oil,cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride,and/or various buffers. Other adjuvants and modes of administration arewell and widely known in the pharmaceutical art.

[0144] Liquid dosage forms for oral administration can includepharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs containing inert diluents commonly used in the art, such aswater. Such compositions can also comprise adjuvants, such as wettingagents, emulsifying and suspending agents, and sweetening, flavoring,and perfuming agents.

[0145] The amount of active ingredient that can be combined with thecarrier materials to produce a single dosage form varies depending uponthe mammalian host treated and the particular mode of administration.

[0146] Preparation of Useful Compounds

[0147] Procedures are provided in the discussion and schemes that followof exemplary chemical transformations that can be useful for thepreparation of compounds of this invention. These syntheses, as with allof the reactions discussed herein, can be carried out under a dry inertatmosphere such a nitrogen or argon if desired. Selected reactions knownto those skilled in the art, can be carried out under a dry atmospheresuch as dry air whereas other synthetic steps, for example, aqueous acidor base ester or amide hydrolyses, can be carried out under laboratoryair.

[0148] Aryl and heteroaryl aryl compounds of this invention as defineabove by W can be prepared in a similar manner as is known to thoseskilled in the art. It should be understood that the discussion belowrefers to both aromatic systems, i. e., heteroaromatics and carbonaromatics, even though only one may be specifically mentioned.

[0149] In general, the choices of starting material and reactionconditions can vary as is well know to those skilled in the art.Usually, no single set of conditions is limiting because variations canbe applied as required and selected by one skilled in the art.Conditions will also will be selected as desired to suit a specificpurpose such as small scale preparations or large scale preparations. Ineither case, the use of less safe or less environmentally soundmaterials or reagents will usually be minimized. Examples of such lessdesirable materials are diazomethane, diethyl ether, heavy metal salts,dimethyl sulfide, some halogenated solvents, benzene and the like. Inaddition, many starting materials can be obtained from commericialsources from catalogs or through other arrangements.

[0150] An aromatic compound of this invention where y is 1 can beprepared as illustrated by converting a carbonyl group bonded to anaromatic (e.g., benzene) ring ortho-substituted with a sulfide. Thesulfide can be prepared via a nucleophilic displacement reaction of theortho fluoride.

[0151] The nucleophile can be a thiol or thiolate anion prepared from aaryl thiol discussed below. A preferred thiol is 4-phenoxybenzenethiolconverted in situ into its anion (thiolate) using potassium carbonate iniso-propyl alcohol at reflux temperature.

[0152] The carbonyl group can be a aldehyde, ketone or carboxylic acidderivative, i.e, a protected carboxylic acid or hydroxamate. A preferredcarbonyl group is an aldehyde and a preferred aldehyde is2-flourobenzaldehyde (ortho-fluorobenzaldehyde). A ketone can beconverted by oxidation into an acid and/or an acid derivative usingreagents such as those discussed below for oxidation of a sulfide orother methods well known in the art. It is noted that this oxidation canaccomplish the oxidation of a sulfide intermediate into thecorresponding sulfone in the same reaction system; i.e., in the samepot, if desired.

[0153] The carbonyl group can then be homologated if desired by reactionwith an anion to form an addition compound. An example of a homologationreagent is a tri-substituted methane compound such as tetraethyldimethylammoniummethylenediphosphonate or trimethylorthoformate.Tetraethyl dimethylammoniummethylenediphosphonate is preferred.Hydrolysis of the reaction product can provide a phenylaceticsubstituted on the aromatic ring with a sulfide of this invention. Acidhydrolysis is preferred. Acids and bases are discussed below andhydrochloric acid is preferred.

[0154] The sulfide can then be oxidized to form a sulfone in one or twosteps as discused below. A preferred oxidizing agent is hydrogenperoxide in acetic acid. The carboxylic acid product or intermediate ofthis invention can then be converted into a protected derivative such asan ester or converted into an activated carboxyl group for reaction withhydroxylamine or and protected hydroxylamine; i.e, a hydroxamate. Theconversion of an acid into a hydroxamate is discussed below as is thecoupling process and removal of a protecting group if required.

[0155] The preferred protected hydroxamic acid derivative is theO-tetrahydropyranyl compound and the preferred coupling procedureutilizes a diimide (EDC), hydroxybenzotriazol and DMF solvent for thecoupling reaction to form the intermediate hydroxybenzotriazol activatedester. A preferred reagent for removal of the THP protecting group ishydrochloric acid.

[0156] Alkylation of the acid at the carbon alpha to the carbonyl groupto form the compounds of this invention can be carried out by firstforming an anion using a base. Bases are discussed below. The preferredbases are strong bases that are either hindered and/or non-nucleophilicsuch as lithium amides, metal hydrides or lithium alkyls.

[0157] Following or during formation of the anion, an alkylating agent(an electrophile) is added that undergoes a nucleophilic substitutionreaction. Non-limiting examples of such alkylating agents arehaloalkanes, dihaloalkanes, haloalkanes also substituted by an activatedester group or activated esters and alkanes substitued with sulfateesters.

[0158] Activated ester groups are well known in the art and can include,for example, an activated ester of an alcohol or a halo compound, anester of a haloalcohol such as a bromo-, iodo- or chloro- derivative ofa tosylate, triflate or mesylate activated ester. Compounds wherein, forexample, R² and R³ are taken together as defined above, can be preparedusing disubstituted alkylating agent; i.e., alkylating agents with twoleaving groups in the same molecule. For example,1,5-dihalo-diethylether or analogous reagents containing one or moresulfate ester leaving groups replacing one or more halogens can be usedto form a pyran ring. A similar sulfur, nitrogen or protected nitrogenalkylating agent can be used to form a thiapyran or piperidine ring. Athiapyran can be oxidized to form a sulfoxide or a sulfone using methodsdiscussed herein. A leaving group in an electrophilic reagent, as iswell known in the art, can be a halogen such as chlorine, bromine oriodine or an active ester such as a sulfonate ester, e.g.,toluenesulfonate (tosylate), triflate, mesylate and the like asdiscussed above.

[0159] The conversion of a cyclic amino acid, heterocycle or alpha-aminoacid defined by R² and R³ that can include an amino acid (nitrogenheterocycle), which can be protected or unprotected, into a compound ofthis invention can be accomplished by alkylation or acylation. Thecarboxylic acid group can be protected with a group such as an alkylester such as methyl, ethyl, tert-butyl and the like or atetrahydropyranyl ester or an arylalkyl ester such as benzyl or it canremain as a carboxylic acid. A protected amino acid such as an ethylester is preferred. The substituent on the heterocycle group is asdefined above and can include hydrogen, tert-butoxycarbonyl (BOC ortBOC), benzyloxycarbonyl (Z) and iso-butyloxycarbonyl groups. Inaddition, the amine can be considered as being a protected intermediateas well as being a product of this invention when the N-substituent isnot hydrogen.

[0160] The nitrogen substituent on the amino acid portion of thecompounds of this invention can be varied. In addition, that variationcan be accomplished at different stages in the synthetic sequence basedon the needs and objectives of the skilled person preparing thecompounds of this invention. The nitrogen side chain variations caninclude replacing the hydrogen substituent with a alkyl, arylalkyl,alkene or alkyne.

[0161] This can be accomplished by methods well known in the art such asalkylation of the amine with an electrophile such as halo- or sulfateester (activated ester) derivative of the desired sidechain. Analkylation reaction is typically carried out in the presence of a basesuch as those discussed above and in a pure or mixed solvent asdiscussed above. A preferred base is postassium carbonate and apreferred solvent is DMF.

[0162] The alkenes, arylalkenes, arylalkynes and alkynes so formed canbe reduced, for example, by hydrogenation with a metal catalyst andhydrogen, to an alkyl or arylalkyl compound of this invention and aalkyne or arylalkyne can be reduced to a alkene, arylalkene, arylakaneor alkane with under catalytic hydrogenation conditions as discussedherein or with an deactivated metal catalyst. Catalysts can include, forexample, Pd, Pd on Carbon, Pt, PtO₂ and the like. Less robust catalysts(deactivated) include such thing as Pd on BaCO3 or Pd with quinolineor/and sulfur.

[0163] An alternative method for alkylation of the amine nitrogen isreductive alkylation. This process, well known in the art, allowstreatment of the secondary amine with an aldehyde or ketone in thepresence of a reducing agent such as borane, borane:THF,borane:pyridine, lithium aluminum hydride. Alternatively, reductivealkylation can be carried out under hydrogenation conditions in thepresence of a metal catalyst. Catalysts, hydrogen pressures andtemperatures are discussed and are well known in the art. A preferredreductive alkylation catalyst is borane:pyridine complex.

[0164] In the case where an intermediate is a carboxylic acid, standardcoupling reactions well known in the art can be used to form thecompounds of this invention including protected intermediates. Forexample, the acid can be converted into an acid chloride, mixedanhydride or activated ester and reacted with an alcohol, amine,hydroxylamine or a protected hydroxylamine in the presence of base toform the amide, ester, hydroxamic acid, protected hydroxamic acid. Thisis the same product as discussed above. Bases are discussed above andinclude N-methyl-morpholine, triethylamine and the like.

[0165] Coupling reactions of this nature are well known in the art andespecially the art related to peptide and amino acid chemistry. Removalof the protecting group can be accomplished, if desired, using standardhydrolysis conditions such as base hydrolysis or exchange or acidexchange or hydrolysis as discussed.

[0166] The Schemes and/or dicussion also illustrate conversion of acarboxylic acid protected as an ester or amide into an hydroxamic acidderivative such as a O-arylalkylether or O-cycloalkoxyalkylether groupsuch as the THP group. Methods of treating an acid or acid derivativewith hydroxylamine or a hydroxylamine derivative to form a hydroxamicacid or hydroxamate derivative are discussed above. Hydroxylamine can beused in an exchange reaction by treatment of a precursor compound wherethe carboxyl is protected as an ester or amide with one or moreequivalents of hydroxylamine hydrochloride or hydroxylamine at roomtemperature or above to provide a hydroxamic acid directly. The solventor solvents, usually protic or protic solvent mixtures such as thoselisted herein.

[0167] This exchange process can be further catalyzed by the addition ofadditional acid. Alternatively, a base such as a salt of an alcohol usedas a solvent, for example, sodium methoxide in methanol, can be used toform hydroxylamine from hydroxylamine hydrochloride in situ which canexchange with an ester or amide. As mentioned above, exchange can becarried out with a protected hydroxyl amine such astetrahydropyranyl-hydroxyamine (THPONH₂), benzylhydroxylamine (BnONH2),O-(trimethylsilyl)hydroxylamine and the like, in which case thecompounds formed are tetrahydropyranyl (THP), benzyl (Bn) or TMShydroxamic acid derivatives. Removal of the protecting groups whendesired, for example, following further transformations in another partof the molecule or following storage, can be accomplished by standardmethods well known in the art such as acid hydrolysis of the THP groupas discussed above or reductive removal of the benzyl group withhydrogen and a metal catalyst such as palladium, platinum, palladium oncarbon or nickel.

[0168] alpha-Amino acids or alpha-hydroxy carboxylic acids or protectedcarboxylic acids, hydroxamates or hydroxamic acid derivatives orintermediates (precursors) of this invention can be prepared bydisplacing, for example, a halogen, sulfate ester or other electrophile,from the alpha carbon of an acid or a derivative as listed. Methods forthe halogenation of acids, esters, acid chlorides and like are wellknown in the art and include, for example, the HVZ reaction, treatmentwith CuCl₂, N-bromo- or N-chloro-succinimide, I₂, carbon tetraiodide orbromide and the like. The halogen can be displaced with a nucleophile inan SN₂ reaction. Nucleophiles can include hydroxide, ammonia or amines.

[0169] The aryl or heteroaryl carboxylic acids of this invention where Yis 0 and z is 1 can be prepared from heteroaryl or aryl fused lactones.An example of a fused lactone is phthalide. A preferred startingmaterial is phthalide. This compound can be treated with an thiol,thiolate or metal -SH in order to undergo a SN₂ displacement at themethylene carbon to provide a sulfide or thiol compound of thisinvention or intermediate to a compound of this invention. A preferredthiol is 4-phenoxybenzenethiol that is used in the presence of potassiumcarbonate as a preferred base. The sulfide can be oxidized, before orafter conversion of the acid to a hydroxamate or hydroxamic acid, to asulfone of this invention. A preferred oxidizing agent ismeta-chloroperbenzoic acid.

[0170] A preferred acid activating group is the chloride prepared byreaction of an acid with oxalyl chloride as a preferred reagent. Aphthalide or a heteroaryl analog of a phthalide can be treated with aLewis acid such as zinc chloride or zinc bromide along with ahalogenating reagent such as phosphorus trichloride or thionyl bromideor the like to form a ortho-(haloalkyl)-aryl acid orortho-(haloalkyl)-heteroaryl acid derivative. Examples includebromomethyl acid bromides and chloromethyl acid chlorides. Thesecarboxylic acids can be derivatized with protecting groups, hydroxamicacids or hydroxamic acid precursors (hydroxamates) or hydrolyzed to theacid as required. A preferred hydroxamate forming reagent isO-(trimethylsilyl)hydroxylamine (TMS-hydroxylamine) and removal of theTMS protecting group is preferably accomplished by acid hydrolysis usinghydrochloric acid.

[0171] Displacement (SN₂) of the halogen in this example by a thiol inthe presence of base or a preformed thiolate can be accomplished asdiscussed and/or shown and as is well known in the art. Again, oxidationof the sulfide can be carried out before or after derivatization of thecarboxylic acid as discussed to prepare the hydroxamic acids of thisinvention. Removal of the protecting groups can be carried out usingacid hydrolysis or reduction as discussed elsewhere in this document.

[0172] The alcohols of this invention can be protected or deprotected asrequired or desired. Protecting groups can include THP ethers, acylatedcompounds and various silyl derivatives. These groups, including thereprotection and removal, are well known in the art.

[0173] Examples of bases that can be used include, for example, metalhydroxides such as sodium, potassium, lithium or magnesium hydroxide,oxides such as those of sodium, potassium, lithium, calcium ormagnesium, metal carbonates such as those of sodium, potassium, lithium,calcium or magnesium, metal bicarbonates such as sodium bicarbonate orpotassium bicarbonate, primary (I°), secondary (II°) or tertiary (III°)organic amines such as alkyl amines, arylalkyl amines, alkylarylalkylamines, heterocyclic amines or heteroaryl amines, ammonium hydroxides orquaternary ammonium hydroxides. As non-limiting examples, such aminescan include triethyl amine, trimethyl amine, diisopropyl amine,methyldiisopropyl amine, diazabicyclononane, tribenzyl amine,dimethylbenzyl amine, morpholine, N-methylmorpholine,N,N′-dimethylpiperazine, N-ethylpiperidine,1,1,5,5-tetramethylpiperidine, dimethylaminopyridine, pyridine,quinoline, tetramethylethylenediamine and the like.

[0174] Non-limiting examples of ammonium hydroxides, usually made fromamines and water, can include ammonium hydroxide, triethyl ammoniumhydroxide, trimethyl ammonium hydroxide, methyldiiospropyl ammoniumhydroxide, tribenzyl ammonium hydroxide, dimethylbenzyl ammoniumhydroxide, morpholinium hydroxide, N-methylmorpholinium hydroxide,N,N-dimethylpiperazinium hydroxide, N-ethylpiperidinium hydroxide, andthe like. As non-limiting examples, quaternary ammonium hydroxides caninclude tetraethyl ammonium hydroxide, tetramethyl ammonium hydroxide,dimethyldiiospropyl ammonium hydroxide, benzymethyldiisopropyl ammoniumhydroxide, methyldiazabicyclononyl ammonium hydroxide, methyltribenzylammonium hydroxide, N,N-dimethylmorpholinium hydroxide, N,N,N′, N′,-tetramethylpiperazenium hydroxide, and N-ethyl-N′-hexylpiperidiniumhydroxide and the like. Metal hydrides, amide or alcoholates such ascalcium hydride, sodium hydride, potassium hydride, lithium hydride,sodium methoxide, potassium tert-butoxide, calcium ethoxide, magnesiumethoxide, sodium amide, potassium diisopropyl amide and the like canalso be suitable reagents. Organometallic deprotonating agents such asalkyl or aryl lithium reagents such as methyl, phenyl, butyl, iso-butyl,sec-butyl or tert-butyl lithium, nodium or potassium salts ofdimethylsulfoxide, Grignard reagents such as methylmagnesium bromide ormethymagnesium chloride, organocadium reagents such as dimethylcadiumand the like can also serve as bases for causing salt formation orcatalyzing the reaction. Quaternary ammonium hydroxides or mixed saltsare also useful for aiding phase transfer couplings or serving as phasetransfer reagents. Preferred base for use in the alkylation reaction islithium diisopropyl amide as mentioned above.

[0175] Reaction media in general can be comprised of a single solvent,mixed solvents of the same or different classes or serve as a reagent ina single or mixed solvent system. The solvents can be protic, non-proticor dipolar aprotic. Non-limiting examples of protic solvents includewater, methanol (MeOH), denatured or pure 95% or absolute ethanol,isopropanol and the like.

[0176] Typical non-protic solvents include acetone, tetrahydrofurane(THF), dioxane, diethylether, tert-butylmethyl ether (TBME), aromaticssuch as xylene, toluene, or benzene, ethyl acetate, methyl acetate,butyl acetate, trichloroethane, methylene chloride, ethylenedichloride(EDC), hexane, heptane, isooctane, cyclohexane and the like. Dipolaraprotic solvents include compounds such as dimethylformamide (DMF),dimethylacetamide (DMAc), acetonitrile, nitromethane, tetramethylurea,N-methylpyrrolidone and the like.

[0177] Non-limiting examples of reagents that can be used as solvents oras part of a mixed solvent system include organic or inorganic mono- ormulti-protic acids or bases such as hydrochloric acid, phosphoric acid,sulfuric acid, acetic acid, formic acid, citric acid, succinic acid,triethylamine, morpholine, N-methylmorpholine, piperidine, pyrazine,piperazine, pyridine, potassium hydroxide, sodium hydroxide, alcohols oramines for making esters or amides or thiols for making the products ofthis invention and the like. Room temperature or less or moderatewarming (−10° C. to 60° C.) are the preferred temperatures of thereaction. If desired, the reaction temperature might be about −78° C. tothe reflux point of the reaction solvent or solvents. The preferredsolvent for an alkylation reaction is tetrahydrofurane (THF).

[0178] Acids are used in many reactions during various synthesis. TheSchemes as well as this discussion preparative methods illustrate aciduse for the removal of the THP protecting group to produce a hydroxamicacid, removal of a tert-butoxy carbonyl group, hydroxylamine/esterexchange and the like. Acid hydrolysis of carboxylic acid protectinggroups or derivatives is well known in the art. These methods, as iswell known in the art, can use acid or acidic catalysts. The acid can bemono-, di- or tri-protic organic or inorganic acids. Examples of acidsinclude hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid,formic acid, citric acid, succinic acid, hydrobromic acid, hydrofluoricacid, carbonic acid, phosphorus acid, p-toluene sulfonic acid,trifluoromethane sulfonic acid, trifluoroacetic acid, difluoroaceticacid, benzoic acid, methane sulfonic acid, benzene sulfonic acid,2,6-dimethylbenzene sulfonic acid, trichloroacetic acid, nitrobenzoicacid, dinitrobenzoic acid, trinitrobenzoic acid, and the like. They canalso be Lewis acids such as aluminum chloride, borontrifluoride,antimony pentafluoride and the like.

[0179] Contemplated compounds can include compounds wherein a nitrogenof an amine is acylated to provide, for example, amino acid carbamates.Non-limiting examples of these carbamates are the carbobenzoxycarbonyl(Z, CBZ, benzyloxycarbonyl), iso-butoxycarbonyl and tert-butoxycarbonyl(BOC, t-BOC) compounds. The materials can be made, as discussed above,at various stages in the synthesis based on the needs and decisions madeby a person skilled in the art using methods well know in the art.

[0180] Useful synthetic techniques and reagents include those used inprotein, peptide and amino acid synthesis, coupling and transformationchemistry. The use of the tert-butoxycarbonyl (BOC) andbenzyloxycarbonyl (Z) as will as their synthesis and removal areexamples of such protection or synthesis schemes. Transformations ofamino acids, amino esters, amino acid hydroxamates, amino acidhydroxamate derivatives and amino acid amides of this invention orcompounds used in this invention is discussed herein or/and shown in theschemes. This includes, for example, active ester or mixed anhydridecouplings wherein preferred bases, if required, are tertiary amines suchas N-methylmorpholine. Reagents for protection of the amine group of theprotected amino acids include carbobenzoxy chloride,iso-butylchloroformate, tert-butoxycarbonyl chloride, di-tert-butyldicarbonate and the like which are reacted with the amine in non-proticor dipolar aprotic solvents such as DMF or THF or mixtures of solvents.

[0181] Removal of protecting groups such as carbamates, silyl groups andbenzyl, p-methoxybenzyl, or other substituted benzyl groups ordiphenylmethyl (benzhydryl) or triphenylmethyl (trityl) can be carriedout at different stages in the synthesis of the compounds of thisinvention as required by methods selected by one skilled in the art.These methods are well known in the art including the amino acid, aminoacid coupling, peptide synthesis, peptide mimetic synthesis art. Removalmethods can include catalytic hydrogenation, base hydrolysis, carbonyladdition reactions, acid hydrolysis and the like. Both the preparationand removal of protecting groups, for example, carbamates, benzyl groupsand/or substitued arylalkyl groups is discussed in Green, T., ProtectingGroups in Organic Chemistry, Second ed., John Wiley & Sons, New York(1991). A preferred method of removal of a BOC group is HCl gas inmethylene chloride which, following normal workup, provides directly anHCl salt of an aminoacid of this invention.

[0182] Sulfone compounds such as those where R¹ is nitrobenzene can beprepared as compounds of this invention by synthesis of a thiol,displacement of an electrophile by the nucleophilic thiol or thiolateand oxidation of the product thiol ether to the sulfone. For example,displacement of the electrophilic group with a nitro-benzene thiol canyield a compound where R¹ is nitrobenzene, whose nitro group can bereduced to provide a useful amino compound wherein R¹ is an aniline. Itshould be noted that nitrobenzenethiol is an example and not to beconsidered as limiting or required. Oxidation of the thioether productcan be carried out as discussed below when desired.

[0183] The reduction of nitro groups to amines is well known in the artwith a preferred method being hydrogenation. There is usually a metalcatalyst such as Rh, Pd, Pt, Ni or the like with or without anadditional support such as carbon, barium carbonate and the like.Solvents can be protic or non-protic pure solvents or mixed solvents asrequired. The reductions can be carried out at atmospheric pressure to apressure of multiple atmospheres with atmospheric pressure to about 40pounds per square inch (psi) preferred.

[0184] The resulting amino group can be alkylated if desired. It canalso be acylated with, for example, an aroyl chloride, heteroarylchloride or other amine carbonyl forming agent to form an R¹ amide ofthis invention. The amino sulfone or thioether can also be reacted witha carbonic acid ester chloride, a sulfonyl chloride, a carbamoylchloride or an isocyanate to produce the corresponding carbamate,sulfonamides, or ureas of this invention. Acylation of amines of thistype are well known in the art and the reagents are also well known.

[0185] Usually these reactions are carried out in aprotic solvents underan inert or/and dry atmosphere at about 45° C. to about −10° C. Anequivalent of a non-competitive base is usually used with sulfonylchloride, acid chloride or carbonyl chloride reagents. Following orbefore this acylation step, synthesis of the hydroxamic acid products ofthis invention can proceed as discussed.

[0186] Other thiol reagents can also be used in the preparation ofcompounds of this invention. Examples are fluoroaryl, fluoroheteroaryl,azidoaryl or azidoheteroaryl or heteroaryl thiol reagents. These thiolscan be used a nucleophiles to as discussed above. Oxidation to thecorresponding sulfone can then be carried out.

[0187] The sulfones, if substituted by a hydrazine or substitutedhydrazine, can be oxidized to a hydrazone of this invention. The fluorosubstituted sulfone can be treated with a nucleophile such as ammonia, aprimary amine, a quaternary ammonium or metal azide salt or a hydrazineunder pressure if desired, to provide an azido, amino, substituted aminoor hydrazino group. Azides can be reduced to an amino group using, forexample, hydrogen with a metal catalyst or metal chelate catalyst or byan activated hydride transfer reagent. The amines can be acylated asdiscussed above.

[0188] Methods of preparing useful aminethiol intermediates includeprotection of an aromatic or heteroaromatic thiol with trityl chlorideto form the trityl thiol derivative, treatment of the amine with asreagent such as an aromatic or heteraromatic acid chloride to form theamide, removal of the trityl group, with acid to form the thiol.Acylating agents include benzoyl chloride and trityl removing reagentsinclude triflouroacetic acid and trisiopropylsilane.

[0189] The fluorine on the fluorosulfones of this invention can also bedisplaced with other aryl or heteroaryl nucleophiles for form compoundsof this invention. Examples of such nucleophiles include salts ofphenols, thiophenols, —OH group containing aromatic heterocycliccompounds or —SH containing heteroaryl compounds. Tautomers of suchgroups azo, hydrazo, —OH or —SH are specifically included as usefulisomers.

[0190] A preferred method of preparing intermediates in the synthesis ofthe substituted sulfones is by oxidation of an appropriate acetophenone,prepared from a flouroacetophenone, with for example, peroxymonosulfate,to form the corresponding phenol-ether. The phenol-ether is convertedinto its dimethylthiocarbamoyl derivative using dimethylthiocarbamoylchloride, rearranged into the dimethylthiocarbamoyl derivative with heatto provide the thiol required for preparation of the thioetherintermediate discussed and/or shown in the schemes.

[0191] The compounds of this invention including protected compounds orintermediates can be oxidized to the sulfones as shown in the schemesand/or discussed above. The selection of the stage of the alternativesynthesis to implement this conversion of sulfides into the sulfones orsulfoxides can be carried out by one skilled in the art.

[0192] Reagents for this oxidation process may, in a non-limitingexample, include peroxymonosulfate (OXONE®), hydrogen peroxide,meta-chloroperbenzoic acid, perbenzoic acid, peracetic acid, perlacticacid, tert-butyl peroxide, tert-butyl hydroperoxide, tert-butylhypochlorite, sodium hypochlorite, hypochlorus acid, sodiummeta-peroiodate, periodic acid, ozone and the like. Protic, non-protic,dipolar aprotic solvents, either pure or mixed, can be chosen, forexample, methanol/water. The oxidation can be carried out at temperatureof about −78° to about 50° degrees centigrade and normally selected froma range −10° C. to about 40° C.

[0193] Preparation of the sulfones can also be carried out in two stepsby the oxidation of a sulfide to a sulfoxide followed by oxidation ofthe sulfoxide to the sulfone. This can occur in one pot or by isolationof the sulfoxide. This latter oxidation can be carried out in a mannersimilar to the oxidation directly to the sulfone except that about oneequivalent of oxidizing agent can be used preferably at a lowertemperature such as about 0° C. Preferred oxidizing agents includeperoxymonosulfate and meta-chloroperbenzoic acid.

[0194] Salts of the compounds or intermediates of this invention areprepared in the normal manner wherein acidic compounds are reacted withbases such as those discussed above to produce metal or nitrogencontaining cation salts. Basic compounds such as amines can be treatedwith an acid to form an amine salt.

[0195] Compounds of the present can possess one or more asymmetriccarbon atoms and are thus capable of existing in the form of opticalisomers as well as in the form of racemic or nonracemic mixturesthereof. The optical isomers can be obtained by resolution of theracemic mixtures according to conventional processes well known in theart, for example by formation of diastereoisomeric salts by treatmentwith an optically active acid or base.

[0196] Examples of appropriate acids are tartaric, diacetyltartaric,dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid and thenseparation of the mixture of diastereoisomers by crystallizationfollowed by liberation of the optically active bases from these salts. Adifferent process for separation of optical isomers involves the use ofa chiral chromatography column optimally chosen to maximize theseparation of the enantiomers.

[0197] Still another available method involves synthesis of covalentdiastereoisomeric molecules, e.g., esters, amides, acetals, ketals, andthe like, by reacting compounds of Formula I with an optically activeacid in an activated form, a optically active diol or an opticallyactive isocyanate. The synthesized diastereoisomers can be separated byconventional means such as chromatography, distillation, crystallizationor sublimation, and then hydrolyzed to deliver the enantiomericaly purecompound. In some cases hydrolysis to the parent optically active drugis not necessary prior to dosing the patient since the compound canbehave as a prodrug. The optically active compounds of Formula I canlikewise be obtained by utilizing optically active starting materials.

[0198] In additon to the optical isomers or potentially optical isomersdiscussed above, other types of isomers are specifically intended to beincluded in this discussion and in this invention. Examples include cisisomers, trans isomers, E isomers, Z isomers, syn- isomers, anti-isomers, tautomers and the like. Aryl, heterocyclo or heteroaryltautomers, heteroatom isomers and ortho, meta or para substitutionisomers are also included as isomers. Solvates or solvent additioncompounds such as hydrates or alcoholates are also specifically includedboth as chemicals of this invention and in, for example, formulations orpharmaceutical compositions for drug delivery.

[0199] Where a substituent is designated as, or can be, a hydrogen, theexact chemical nature of a substituent which is other than hydrogen atthat position, e.g., a hydrocarbyl radical or a halogen, hydroxy, aminoand the like functional group, is not critical so long as it does notadversely affect the overall activity and/or synthesis procedure. Forexample, two hydroxyl groups, two amino groups, two thiol groups or amixture of two hydrogen-heteroatom groups on the same carbon are knownnot to be stable without protection or as a derivative.

[0200] The chemical reactions described above are generally disclosed interms of their broadest application to the preparation of the compoundsof this invention. Occasionally, the reactions can not be applicable asdescribed to each compound included within the disclosed scope. Thecompounds for which this occurs will be readily recognized by thoseskilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to thoseskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilypreparable from known starting materials.

[0201] Other compounds of this invention that are acids can also formsalts. Examples include salts with alkali metals or alkaline earthmetals, such as sodium, potassium, calcium or magnesium or with organicbases or basic quaternary ammonium salts.

[0202] In some cases, the salts can also be used as an aid in theisolation, purification or resolution of the compounds of thisinvention.

BEST MODE FOR CARRYING OUT THE INVENTION

[0203] Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, utilize the presentinvention to its fullest extent. The following preferred specificembodiments are, therefore, to be construed as merely illustrative, andnot limiting of the remainder of the disclosure in any way whatsoever.

EXAMPLE 1 N-hydroxy-2-[[(4-phenoxyphenyl)sulfonyl]methyl]benzamide

[0204]

[0205] Part A: To a solution of phthalide (6.30 g, 47.0 mmol) in DMF(100 mL) was added K₂CO₃ (10.0 g, 49.4 mmol) and 4-(phenoxy)benzenethiol(9.59 g, 49.4 mmol) and the solution was heated to one hundred degreesCelsius for 2 hours. The solution was diluted with H₂O and acidifiedwith 1N HCl to pH=1. The resulting tan solid was collected and washedwith H₂O. The solid was dissolved into ethyl ether and dried over MgSO₄.Concentration in vacuo followed by recrystallization (ethylether/hexane) provided the sulfide as a white solid (9.12 g, 58%).MS(CI) MH⁺ calculated for C₂₀H₁₆O₃S: 337, found 337. Analyticalcalculation for C₂₀H₁₆O₃S: C, 71.41; H, 4.79; S, 9.53.

[0206] Found: C, 71.28; H, 4.67; S, 9.19.

[0207] Part B: To a solution of the sulfide of part A (3.00 g, 8.92mmol) in dichloromethane (28 mL) and DMF (1 drop) was added oxalylchloride (1.08 mL, 12.4 mmol) and the solution was stirred for 1 hour.After concentration in vacuo the residue was dissolved intodichloromethane (16 mL) and the solution was cooled to zero degreesCelsius. Tetramethylsilyl hydroxylamine (2.55 mL, 20.8 mmol) was addedand the solution was stirred for 1.5 hours. The solution was dilutedwith dichloromethane and washed with 1N HCl, H₂O and saturated NaCl anddried over MgSO₄. Chromatography (on silica, ethylacetate/hexane/toluene) provide the hydroxylamine as a clear paste (970mg, 31%).

[0208] Part C: To a solution of the hydroxylamine of part B (970 mg,2.76 mmol) in dichloromethane (25 mL) cooled to zero degrees Celsius wasadded 3-chloroperbenzoic acid (60%, 2.14 g, 7.45 mmol) and the solutionwas stirred for 3 hours at ambient temperature. The solution was dilutedwith ethyl ether and washed with saturated Na₂SO₃, saturated NaHCO₃ andsaturated NaCl and dried over MgSO₄. Reverse phase chromatography (onsilica, acetonitrile/H₂O) provided the title compound as a white solid(345 mg, 33%). MS(CI) MH⁺ calculated for C₂₀H₁₇NO₅S: 384, found 384.Analytical calculation for C₂₀H₁₇NO₅S.0.3H₂O: C, 61.70; H, 4.56; N,3.60; S, 8.25.

[0209] Found: C, 61.74; H, 4.42; N, 3.61; S, 8.31.

EXAMPLE 2 N-hydroxy-2-[(4-phenoxyphenyl)sulfonyl]benzeneacetamide

[0210]

[0211] Part A: To a solution of 4-(phenoxy)benzenethiol (6.06 g, 30.0mmol) and K₂CO₃ (4.55 g, 33.0 mmol) in isopropanol (30 mL) was added2-fluorobenzaldehyde (3.2 mL, 30.0 mmol). The solution was refluxed for20 hours. The reaction was quenched by the addition of ice-H₂O and wasextracted with CHCl₃. The organic layer was dried over MgSO₄. Filtrationthrough a pad of silica gel provided the sulfide as a yellow solid (7.43g, 81%).

[0212] Part B: A solution of NaH (60% dispersion in mineral oil, washedwith hexane, 264 mg, 6.6 mmol) in THF (12 mL) was cooled to zero degreesCelsius and tetraethyl dimethylammoniummethylene diphosphonate (1.99 g,6.0 mmol) was added. The solution was warmed to ambient temperature andthe sulfide of part A (1.84 g, 6.0 mmol) was added. The solution wasstirred for 4 hours at ambient temperature. The solution was extractedwith ethyl acetate and washed with H₂O and dried over MgSO₄.Concentration in vacuo provided a brown oil which was dissolved in 6MHCl (10 mL) and the solution was heated to one hundred degrees Celsiusfor 1 hour. The solution was extracted with CHCl₃ and the organic layerwas dried over MgSO₄. Concentration in vacuo provided the acid as an oil(918 mg, 48%).

[0213] Part C: To a solution of the acid of part B (918 mg, 3 mmol) inacetic acid (30 mL) was added 30% hydrogen peroxide (1.2 mL, 12 mmol)and the solution was heated to one hundred degrees Celsius for 40minutes. The solution was lyophilized and chromatography (hexane/ethylacetate) provided the sulfone as a foam (697 mg, 63%).

[0214] Part D: To a solution of the sulfone of part C (695 mg, 1.89mmol) in acetonitrile (2 mL) was added tetrahydropyranyl hydroxylamine(270 mg, 2.3 mmol). After 5 minutes EDC (442 mg, 2.3 mmol) was added andthe solution was stirred for 3 hours. The solution was concentrated invacuo and the residue was partitioned between ethyl acetate and H₂O. Theorganic layer was dried over MgSO₄. Chromatography (on silica gel, ethylacetate/hexane) provided the ester as a white foam (688 mg, 77%).

[0215] Part E: To a solution of the ester of part D (565 mg, 1.2 mmol)in methanol (10 mL) was added p-toluenesulfonic acid (25 mg) and thesolution was stirred at ambient temperature for 2 hours. The solutionwas concentrated in vacuo and chromatography (chloroform/methanol)provided the title compound as a white solid (339 mg, 74%).

Comparative Examples EXAMPLE 3 N-hydroxy-2-[[4-(phenylmethyl)-1-piperidinyl]sulfonyl]benzamide

[0216]

[0217] Part A: To a solution of 2-chlorosulfonylbenzoic acid ethylester, prepared per Nagasawa, et. al. J. Med. Chem. 1995, 38, 1865-1871,(5.80 g, 23.0 mmol) in acetonitrile (50 mL) was added 4-benzylpiperidine(4.38 mL, 25 mmol), triethylamine (3.78 mL, 27 mmol) and4-dimethylaminopyridine (50 mg). The solution was stirred for 4 hours atambient temperature and concentrated in vacuo. The residue was dissolvedinto 1N HCl and extracted with ethyl acetate. The organic layer wasdried over MgSO₄ and filtered through a pad of silica gel to provide thesulfonamide as an oil (7.45 g, 84%).

[0218] Part B: To a solution of the sulfonamide of part A (1.08 g, 2.80mmol) in methanol (50 mL) and H₂O (20 mL) was added KOH (2 g) and thesolution was stirred for 3 hours at ambient temperature. The solutionwas concentrated in vacuo and the remaining aqueous solution wasacidified with 1N HCl. The solution was extracted with chloroform andthe organic layer was dried over MgSO₄ and filtered through a pad ofsilica gel. Concentration in vacuo provided the acid as a white foam(996 mg, quantitative yield).

[0219] Part C: To a solution of the acid of part B (415 mg, 1.2 mmol) inacetonitrile (2 mL) was added tetrahydropyranyl hydroxylamine (200 mg,1.7 mmol). After the solution was stirred for 5 minutes EDC (325 mg, 1.7mmol) was added and the solution was stirred for 3 hours at ambienttemperature. The solution was concentrated in vacuo and the residue wasdissolved into H₂O and extracted with ethyl acetate. The organic layerwas dried over MgSO₄. Chromatography (on silica, ethyl acetate/hexane)provided the ester as a white solid (437 mg, 82%).

[0220] Part D: To a solution of the ester of part C (437 mg, 0.98 mmol)in methanol (5 mL) was added p-toluenesulfonic acid (40 mg) and thesolution was stirred for 1 hour at ambient temperature. The solution wasconcentrated in vacuo. Chromatography (ethyl acetate,1% NH₄OH) providedthe title compound as an oil (122 mg, 34%)

EXAMPLE 4 2-[([1,1′-biphenyl]-4-ylmethyl)sulfonyl]-N-hydroxybenzamide

[0221]

[0222] Part A: To a solution of thiosalicylic acid (5.00 g, 32.4 mmol)and 4-phenylbenzyl chloride (6.57 g, 32.4 mmol) in ethanol (81 mL) andH₂O (40 mL) was added K₂CO₃ (4.48 g, 32.4 mmol) and the solution washeated to reflux for 2 hours. Upon cooling to ambient temperature awhite solid formed. To this mixture is added 1N HCl (200 mL) and vacuumfiltration provided the sulfide as a white solid (7.32 g, 70%).

[0223] Part B: To a solution of the sulfide of part A (1.00 g, 3.12mmol) in formic acid (17 mL) heated to fifty degrees Celsius was added30% hydrogen peroxide (1.16 mL). The solution was stirred at fifty-fivedegrees Celsius for 3 hours followed by 40 hours at ambient temperature.The solution was concentrated and reverse phase chromatography(acetonitrile/H₂O) provided the sulfone as a white solid (500 mg, 45%).

[0224] Part C: To a solution of the sulfone of part B (500 mg, 1.42mmol) in DMF (2.8 mL) was added tetrahydropyranyl hydroxylamine (173 mg,1.48 mmol), N-hydroxybenzotriazole (211 mg, 1.56 mmol) and EDC (299 mg,1.56 mmol) and the solution was stirred for 18 hours at ambienttemperature. The solution was concentrated in vacuo and the residue wasdissolved into H₂O. The solution was extracted with ethyl acetate andthe organic layer was washed with 1N HCl, saturated NaHCO₃, H₂O andsaturated NaCl and dried over MgSO₄. Concentrated in vacuo provided theester as a white solid (571 mg, 89%). MS(CI) MH⁺ calculated forC₂₅H₂₅NO₅S: 452, found 452.

[0225] Part D: To a solution of the ester of part C (570 mg, 1.26 mmol)in methanol (10 mL) was added p-toluenesulfonic acid (15 mg) and thesolution was stirred at ambient temperature for 1.5 hours. The solutionwas concentrated in vacuo and reverse phase chromatography(acetonitrile/H₂O) provided the title compound as a white solid (244 mg,53%). MS(EI) M⁺ calculated for C₂₀H₁₇NO₄S: 367, found 367. Analyticalcalculation for C₂₀H₁₇NO₄S: C, 65.38; H, 4.66; N. 3.81.

[0226] Found: C, 65.01; H, 4.64; N. 4.04.

EXAMPLE 5 N-hydroxy-2-[[(4-phenoxyphenyl)sulfonyl]amino]benzamide

[0227]

[0228] Part A: To a solution of isatoic anhydride (1.00 g, 6.13 mmol) inacetonitrile (3 mL) was added tetrahydropyranyl hydroxylamine (1.56 g,6.74 mmol) and the solution was heated to reflux for 2 hours. Thesolution was concentrated in vacuo and recrystallization of the residue(ethyl acetate/hexane) provided the ester as a white solid (760 mg, 52%). MS(CI) MH⁺ calculated for C₁₂H₁₆N₂O₃: 237, found 237. Analyticalcalculation for C₁₂H₁₆N₂O₃: C, 61.00; H, 6.83; N, 11.86. Found: C,60.82; H, 6.95; N, 11.76.

[0229] Part B: To a solution of 4-(phenoxy)benzene sulfonyl chloride,prepared per J. Am. Chem. Soc., 1931, 93, 1112-1115) (341 mg, 1.27 mmoL)in pyridine (2 mL) cooled to zero degrees Celsius was added the ester ofpart B (300 mg, 1.27 mmol) and the solution was stirred at zero degreesCelsius for 3 hours. The solution was concentrated in vacuo and theresidue was dissolved in 1N HCl and was extracted with ethyl acetate.The organic layer was washed with 1N HCl, H₂O and saturated NaCl anddried over MgSO₄. Chromatography (on silica gel, ethyl acetate/hexane)provided the sulfone as a white solid (321 mg, 54%). MS(CI) MH⁺calculated for C₂₄H₂₄N₂O₆S: 469, found 469. Analytical calculation forC₂₄H₂₄N₂O₆S: C, 61.53; H, 5.16; N, 5.98; S, 6.84. Found: C, 61.10; H,4.93; N, 5.86; S, 6.41.

[0230] Part C: Into a solution of the sulfone of part B (320 mg, 0.68mmol) in methanol (3 mL) cooled to zero degrees Celsius was bubbled HClgas for 5 minutes. The solution was concentrated in vacuo and theresidue was triturated with ethyl ether. Collection by vacuum filtrationprovided the title compound as a pink solid (163 mg, 62%). MS(CI) MH⁺calculated for C₁₉H₁₆N₂O_(d)S: 385, found 385. Analytical calculationfor C₁₉H₁₆N₂O₆S.0.2H₂O: C, 58.81; H, 4.26; N, 7.22; S, 8.26. Found: C,58.88; H, 4.37; N, 6.98; S, 7.83.

EXAMPLE 6 N-hydroxy-2-[[(4-methoxyphenyl)sulfonyl]methyl]benzamide

[0231]

[0232] Part A: A 500 mL round bottom flask equipped with magnetic stirbar and N₂ inlet was charged with 1.5 mL (1.7 g, 12.0 mM)4-methoxybenzenethiol and 2.5 g (10.9 mM) methyl (2-bromomethyl)benzoatein acetone (100 mL). The solution was treated with 1.8 g (13.1 mM)potassium carbonate and heated at 55° C. in an oil bath. The reactionmixture was stirred at 55° C. for 17 hrs, then concentrated in vacuo.The residue was partitioned between EtOAc and H₂O, the layers wereseparated and the aqueous layer was extracted with EtOAc (1×), theorganic phases were combined, washed with 5% citric acid solution,saturated sodium bicarbonate solution and brine, dried (Na₂SO₄), andconcentrated in vacuo to yield 3.3 g of product suitable for the nextreaction.

[0233] Part B: A 500 mL round bottom flask equipped with magnetic stirbar and N₂ inlet was charged with 3.1 g (10.8 mM) of product from Part Ain 90 mL MeOH. The solution was then treated with 15 mL water and 13.9 g(22.6 mM) Oxone®. The reaction mixture was stirred 17 hrs, thenfiltered. The filter cake was washed with MeOH, and the filtrate wasconcentrated in vacuo. The residue was partitioned between EtOAc andH₂O, the layers were separated and the aqueous layer was extracted withEtOAc (2×). The organic phases were combined, washed with saturatedsodium bicarbonate solution and brine, dried (MgSO₄), and concentratedin vacuo to yield the 3.3 g of crude product. This was chromatographedon silica gel using 25-45% ethyl acetate/hexane to yield 2.1 g of pureproduct, m/z=321 (M+H).

[0234] Part C: A 250 mL round bottom flask equipped with magnetic stirbar and N₂ inlet was charged with 2.1 g (6.6 mM) of product from Part Bin acetic acid (25 mL) and conc. HCl solution (25 mL) and the solutionwas heated to reflux for a total of 24 hours. The reaction mixture wasconcentrated in vacuo, then two aliquots of toluene were added andstripped, then dried under high vacuum to yield 2.0 g of productsuitable for the next reaction.

[0235] Part D: A 2-necked 50 mL round bottom flask equipped withaddition funnel, thermometer, magnetic stir bar and N₂ inlet was chargedwith 1.0 mL of DMF in 10 mL CH₂Cl₂. The solution was cooled in an icebath, then treated with 3.5 mL (0.9 g, 6.9 mM) of a 2.0 M oxalylchloride solution in CH₂Cl₂, then with a solution of 1.0 g (3.3 mM) ofproduct from Part C in 5 mL DMF. The bath was removed and the reactionwas stirred for 1 hour. This reaction mixture was added to a 2-necked100 mL round-bottomed flask equipped with addition funnel, thermometer,magnetic stir bar and N₂ inlet and containing a cooled solution of 2.1mL (1.1 g, 37.7 mM) of 50% aqueous hydroxylamine in THF (25 mL). Thebath was then removed and the reaction mixture was stirred for 2 hours.The reaction was filtered, the filtrate was concentrated in vacuo, theresidue was partitioned between EtOAc/water, the layers were separated,the aqueous layer was extracted with EtOAc (1×), the organic phases werecombined and washed with water and brine, dried (Na₂SO₄) andconcentrated in vacuo to yield 1.3 g of crude product. This waschromatographed on silica gel using 80% ethyl acetate/hexane to yield0.5 g of pure product, m/z=328 (M+Li).

EXAMPLE 7 N-hydroxy-2-[(4-methoxyanilino)sulfonyl]benzamide

[0236]

[0237] Part A: A 3-necked 100 mL round bottom flask equipped withaddition funnel, thermometer, magnetic stir bar and N₂ inlet was chargedwith 0.5 g (4.3 mM) of p-anisidine and 1.8 mL (1.3 g, 12.8 mM)triethylamine in CH₂Cl₂ (20 mL). The solution was cooled in an ice bath,then treated with a solution of 1.0 g (4.3 mM) methyl(2-chlorosulfonyl)benzoate in CH₂Cl₂ (10 mL). The reaction mixture wasstirred for 17 hrs, then concentrated in vacuo. The residue waspartitioned between EtOAc and H₂O, the layers were separated and theorganic phase was washed with 5% citric acid solution, saturated sodiumbicarbonate solution and brine, dried (Na₂SO₄), and concentrated invacuo to yield 0.9 g of crude product. This was chromatographed onsilica gel using 20-30% ethyl acetate/hexane to yield 0.7 g of pureproduct, m/z=328 (M+Li).

[0238] Part B: A 100 mL round bottom flask equipped with magnetic stirbar and N₂ inlet was charged with 0.7 g (2.1 mM) of the product fromPart A and 0.7 g (10.2 mM) of hydroxylamine hydrochloride in 10 mL MeOH.The reaction was cooled to 0^(l) C and charged with 0.4 g (16.4 mM) ofsodium metal. After stirring for 17 hrs, the reaction was concentratedin vacuo, the residue was slurried in 20 mL of water, then acidifiedusing 2N HCl solution. The aqueous slurry was extracted with EtOAc (3×).The organic layers were combined and washed with brine, dried (Na₂SO₄),and concentrated in vacuo to yield 0.6 g of crude product. The additionof methylene chloride to the crude product precipitated an off-whitesolid. Filtration gave 0.2 g of pure product, m/z=323 (M+Li).

EXAMPLE 8 N-hydroxy-2-[(benzylamino)sulfonyl]benzamide

[0239]

[0240] Part A: A 3-necked 100 mL round bottom flask equipped withaddition funnel, thermometer, magnetic stir bar and N₂ inlet was chargedwith 0.5 mL (0.5 g, 4.3 mM) of benzylamine and 1.8 mL (1.3 g, 12.8 mM)triethylamine in CH₂Cl₂ (20 mL). The solution was cooled in an ice bath,then treated with a solution of 1.0 g (4.3 mM) methyl(2-chlorosulfonyl)benzoate in CH₂Cl₂ (10 mL). The reaction mixture wasstirred for 2 hrs, then concentrated in vacuo. The residue waspartitioned between EtOAc and H₂O, the layers were separated and theorganic phase was washed with 5% citric acid solution, saturated sodiumbicarbonate solution and brine, dried (Na₂SO₄), and concentrated invacuo to yield 0.9 g of crude product. This was chromatographed onsilica gel using 20% ethyl acetate/hexane to yield 0.7 g of pureproduct, m/z=312 (M+Li).

[0241] Part B: A 100 mL round bottom flask equipped with magnetic stirbar and N₂ inlet was charged with 0.7 g (2.1 mM) of the product fromPart A and 0.7 g (10.6 mM) of hydroxylamine hydrochloride in 10 mL MeOH.The reaction was cooled to 0^(l)C and charged with 0.4 g (17.0 mM) ofsodium metal. After stirring for 17 hrs, the reaction was concentratedin vacuo, the residue was slurried in 20 mL of water, then acidifiedusing 2N HCl solution. The aqueous slurry was extracted with EtOAc (3×).The organic layers were combined and washed with brine, dried (Na₂SO₄),and concentrated in vacuo to yield 0.3 g of crude product. The additionof methylene chloride to the crude product precipitated a white solid.Filtration gave 0.1 g of pure product, m/z=307 (M+H).

EXAMPLE 9 In Vitro Metalloprotease Inhibition

[0242] The compounds prepared in the manner described in Examples 1 to 9were assayed for activity by an in vitro assay. Following the proceduresof Knight et al., FEBS Lett. 296(3):263 (1992). Briefly,4-aminophenylmercuric acetate (APMA) or trypsin activated MMPs wereincubated with various concentrations of the inhibitor compound at roomtemperature for 5 minutes.

[0243] More specifically, recombinant human MMP-13 and MMP-1 enzymeswere prepared in laboratories of the assignee. MMP-13 was expressed inbaculovirus as a proenzyme, and purified first over a heparin agarosecolumn and then over a chelating zinc chloride column. The proenzyme wasactivated by APMA for use in the assay. MMP-1 expressed in transfectedHT-1080 cells was provided by Dr. Howard Welgus of WashingtonUniversity, St. Louis, Mo. The enzyme was also activated using APMA andwas then purified over a hydroxamic acid column.

[0244] The enzyme substrate is a methoxycoumarin-containing polypeptidehaving the following sequence:

[0245] MCA-ProLeuGlyLeuDpaAlaArgNH², wherein MCA is methoxycoumarin andDpa is 3-(2,4-dinitrophenyl)-L-2,3-diaminopropionyl alanine. Thissubstrate is commercially available from Baychem as product M-1895.

[0246] The buffer used for assays contained 100 mM Tris-HCl, 100 mMNaCl, 10 mM CaCl₂ and 0.05 percent polyethyleneglycol (23) lauryl etherat a pH value of 7.5. Assays were carried out at room temperature, anddimethyl sulfoxide (DMSO) at a final concentration of 1 percent was usedto dissolve inhibitor compound.

[0247] The assayed inhibitor compound in DMSO/buffer solution wascompared to an equal amount of DMSO/buffer with no inhibitor as controlusing Microfluor™ White Plates (Dynatech). The inhibitor or controlsolution was maintained in the plate for 10 minutes and the substratewas added to provide a final concentration of 4 μM.

[0248] In the absence of inhibitor activity, a fluorogenic peptide wascleaved at the gly-leu peptide bond, separating the highly fluorogenicpeptide from a 2,4-dinitrophenyl quencher, resulting in an increase offluorescence intensity (excitation at 328 nm/emission at 415 nm).Inhibition was measured as a reduction in fluorescent intensity as afunction of inhibitor concentration, using a Perkin Elmer L550 platereader. The IC₅₀ values were calculated from those values. The resultsare set forth in the Inhibition Table (Table 38) below, reported interms of IC₅₀ to three significant figures. Inhibition Table 38 (IC₅₀values in nM) Example MMP-13 MMP-1 MMP-2 1 45 >10,000 10 2 2 900 0.3 31000 >10,000 148 4 >10,000 >10,000 >10,000 5 >10,000 >10,000 3500 64000 >10,000 — 7 >10,000 >10,000 — 8 >10,000 >10,000 —

EXAMPLE 10 In Vivo Angiogenesis Assay

[0249] The study of angiogenesis depends on a reliable and reproduciblemodel for the stimulation and inhibition of a neovascular response. Thecorneal micropocket assay provides such a model of angiogenesis in thecornea of a mouse. See, A Model of Angiogenesis in the Mouse Cornea;Kenyon, B. M., et al., Investigative Ophthalmology & Visual Science,July 1996, Vol. 37, No. 8.

[0250] In this assay, uniformly sized Hydron™ pellets containing bFGFand sucralfate are prepared and surgically implanted into the stromamouse cornea adjacent to the temporal limbus. The pellets are formed bymaking a suspension of 20 μL sterile saline containing 10 μg recombinantbFGF, 10 mg of sucralfate and 10 μL of 12 percent Hydron™ in ethanol.The slurry is then deposited on a 10×10 mm piece of sterile nylon mesh.After drying, the nylon fibers of the mesh are separated to release thepellets.

[0251] The corneal pocket is made by anesthetizing a 7 week old C57Bl/6female mouse, then proptosing the eye with a jeweler's forceps. Using adissecting microscope, a central, intrastromal linear keratotomy ofapproximately 0.6 mm in length is performed with a #15 surgical blade,parallel to the insertion of the lateral rectus muscle. Using a modifiedcataract knife, a lamellar micropocket is dissected toward the temporallimbus. The pocket is extended to within 1.0 mm of the temporal limbus.A single pellet is placed on the corneal surface at the base of thepocket with a jeweler's forceps. The pellet is then advanced to thetemporal end of the pocket. Antibiotic ointment is then applied to theeye.

[0252] Mice are dosed on a daily basis for the duration of the assay.Dosing of the animals is based on bioavailability and overall potency ofthe compound. an exemplary dose is 50 mg/kg bid, po. Neovascularizationof the corneal stroma begins at about day three and is permitted tocontinue under the influence of the assayed compound until day five. Atday five, the degree of angiogenic inhibition is scored by viewing theneovascular progression with a slit lamp microscope.

[0253] The mice are anesthetized and the studied eye is once againproptosed. The maximum vessel length of neovascularization, extendingfrom the limbal vascular plexus toward the pellet is measured. Inaddition, the contiguous circumferential zone of neovascularization ismeasured as clock hours, where 30 degrees of arc equals one clock hour.The area of angiogenesis is calculated as follows.${area} = \frac{\left( {0.4 \times {clock}\quad {hours} \times 3.14 \times {vessel}\quad {length}\quad \left( {{in}\quad {mm}} \right)} \right)}{2}$

[0254] The studied mice are thereafter compared to control mice and thedifference in the area of neovascularization is recorded. A contemplatedcompound typically exhibits about 25 to about 75 percent inhibition,whereas the vehicle control exhibits zero percent inhibition.

[0255] From the foregoing, it will be observed that numerousmodifications and variations can be effectuated without departing fromthe true spirit and scope of the novel concepts of the presentinvention. It is to be understood that no limitation with respect to thespecific example presented is intended or should be inferred. Thedisclosure is intended to cover by the appended claims all suchmodifications as fall within the scope of the claims.

What is claimed is:
 1. A compound corresponding to Formula I:

wherein y and z are each zero or one and the sum of z+y is one; the ring structure W is a 5- or 6-membered divalent aromatic or heteroaromatic ring; R¹ is a substituent containing a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bonded directly to the depicted SO₂-group and having a length greater than about that of a hexyl group and less than about that of an eicosyl group, said R¹ defining a three-dimensional volume, when rotated about an axis drawn through the SO₂-bonded 1-position and the 4-position of a 6-membered ring radical or drawn through the SO₂-bonded 1-position and the center of 3,4-bond of a 5-membered ring radical, whose widest dimension in a direction transverse to the axis of rotation is about that of one furanyl ring to about that of two phenyl rings; and R² and R³ are independently hydrido, C₁-C₄ hydrocarbyl, hydroxyl or amino, or R² and R³ together with the depicted carbon atom to which they are bonded form a 6-membered heterocyclic ring in which the heteroatom is oxygen, sulfur or nitrogen, said heteroatom being optionally substituted with one or two oxygens when sulfur and being optionally substituted with a moiety selected from the group consisting of a C₁-C₄ hydrocarbyl, C₃-C₆ cyclohydrocarbyl, C₁-C₄ acylhydrocarbyl, and sulfonyl C₁-C₄ hydrocarbyl group when nitrogen.
 2. The compound according to claim 1 wherein said 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical of R¹ is substituted with a substituent, R^(4,)that has a chain length of 3 to about 14 carbon atoms.
 3. The compound according to claim 2 wherein said R⁴ substituent is selected from the group consisting of a phenyl group, a phenoxy group, a thiophenoxy group, an anilino group, a phenylazo group, a phenylureido, a benzamido, a nicotinamido, an isonicotinamido, a picolinamido group, a heterocyclo, heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arylhydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonylhydrocarbyl, arylazoaryl, arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl, heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroarylhydrocarbylamino, and a heteroarylthio group.
 4. The compound according to claim 3 wherein said R⁴ substituent is itself substituted by one or more substituents selected from the group consisting of a halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclic, heteroaryl, hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhydrocarboyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl, hydrocarbylhydroxycarbonyl2hydrocarbylthio, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino and N-monosubstituted or N,N-disubstituted aminohydrocarbyl group, wherein the substituent(s) on the nitrogen are selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring group.
 5. A compound corresponding to Formula I:

wherein y and z are each zero or one and the sum of z+y is one; the ring structure W is a 5- or 6-membered divalent aromatic or heteroaromatic ring; R¹ is a substituent containing a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bonded directly to the depicted SO₂-group that is itself substituted at its own 4-position when a 6-membered ring and at its own 3- or 4-position when a 5-membered ring with a substituent R⁴ selected from the group consisting of one other single-ringed cyclohydrocarbyl, heterocyclo, aryl or heteroaryl group, a C₃-C₁₄ hydrocarbyl group, a C₂-C₁₄ hydrocarbyloxy group, a phenoxy group, a thiophenoxy group, a 4-thiopyridyl group, a phenylazo group, a phenylureido group, a nicotinamido group, an isonicotinamido group, a picolinamido group, an anilino group and a benzamido group; and R² and R³ are independently hydrido, C₁-C₄ hydrocarbyl, hydroxyl or amino, or R² and R³ together with the depicted carbon atom to which they are bonded form a 6-membered heterocyclic ring in which the heteroatom is oxygen, sulfur or nitrogen, said heteroatom being optionally substituted with one or two oxygens when sulfur and being optionally substituted with a moiety selected from the group consisting of a C₁-C₄ hydrocarbyl, C₃-C₆ cyclohydrocarbyl, C₁-C₄ acylhydrocarbyl, and sulfonyl C₁-C₄ hydrocarbyl group when nitrogen.
 6. The compound according to claim 5 wherein said R¹ substituent is PhR⁴ in which Ph is phenyl substituted with R⁴ at the 4-position, and said R⁴ is a phenyl, phenoxy, thiophenoxy, phenylazo, benzamido, anilino, nicotinamido, isonicotinamido, picolinamido or phenylureido group that is optionally substituted at the meta- or para-position or both with a moiety that is selected from the group consisting of a halogen, a C₁-C₉ hydrocarbyloxy group, a C₁-C₁₀ hydrocarbyl group, a di- C₁-C₉ hydrocarbylamino group, a carboxyl C₁-C₈ hydrocarbyl group, a C₁-C₄ hydrocarbyloxy carbonyl C₁-C₄ hydrocarbyl group, a C₁-C₄ hydrocarbyloxycarbonyl C₁-C₄ hydrocarbyl group and a carboxamido C₁-C₈ hydrocarbyl group, or is substituted at the meta- and para-positions by two methyl groups or by a methylenedioxy group.
 7. The compound according to claim 5 wherein z is one and y is zero.
 8. The compound according to claim 5 wherein y is one and z is zero.
 9. The compound according to claim 5 wherein said R¹ substituent has a length greater than that of an octyl group and less than that of a stearyl group.
 10. A compound corresponding to Formulas II or III:

wherein the ring structure W is a 5- or 6-membered divalent aromatic or heteroaromatic; R¹ is a substituent containing a single cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bonded directly to the depicted SO₂-group that is itself substituted at its own 4-position when a 6-membered ring and at its own 3- or 4-position when a 5-membered ring with a substituent R⁴ selected from the group consisting of one other single-ringed aryl or heteroaryl group, a C₃-C₁₄ hydrocarbyl group, a C₂-C₁₄ hydrocarbyloxy group, a phenoxy group, a thiophenoxy group, a 4-thiopyridyl group, a phenylazo group, a phenylureido group, a nicotinamido group, an isonicotinamido group, a picolinamido group, an anilino group and a benzamido group; R² and R³ are independently hydrido, C₁-C₄ hydrocarbyl, hydroxyl or amino, or R² and R³ together with the depicted carbon atom to which they are bonded form a 6-membered heterocyclic ring in which the heteroatom is oxygen, sulfur or nitrogen, said heteroatom being optionally substituted with one or two oxygens when sulfur and being optionally substituted with a moiety selected from the group consisting of a C₁-C₄ hydrocarbyl, C₃-C₆ cyclohydrocarbyl, C₁-C₄ acylhydrocarbyl, and sulfonyl C₁-C₄ hydrocarbyl group when nitrogen.
 11. The compound according to claim 10 wherein said R⁴ is a phenyl, phenoxy, anilino, thiophenoxy, benzamido, nicotinamido, isonicotinamido, picolinamido or phenylureido group that is itself optionally substituted at meta or para position or both with a moiety that is selected from the group consisting of a halogen, a C₁-C₉ hydrocarbyloxy group, a C₁-C₁₀ hydrocarbyl group, a di-C₁-C₉ hydrocarbylamino group, a carboxyl C₁-C₈ hydrocarbyl group, a C₁-C₄ hydrocarbyloxy carbonyl C₁-C₄ hydrocarbyl group, a C₁-C₄ hydrocarbyloxycarbonyl C₁-C₄ hydrocarbyl group, and a carboxamido C₁-C₈ hydrocarbyl group, or is substituted at the meta- and para-positions by two methyl groups or by a C₁-C₂ alkylenedioxy group.
 12. The compound according to claim 11 wherein said R⁴ is a phenoxy or thiophenoxy group that is unsubstituted.
 13. The compound according to claim 10 that corresponds in structure to Formula II.
 14. The compound according to claim 10 that corresponds in structure to Formula III.
 15. The compound according to claim 10 wherein R² and R³ together with the carbon atom to which they are bonded form a 4-tetrahydropyranyl or 4-piperidinyl group, said 4-piperidinyl group when present being optionally substituted with a moiety R⁵ selected from the group consisting of a C₁-C₄ hydrocarbyl, C₃-C₆ cyclohydrocarbyl, C₁-C₄ acylhydrocarbyl, and sulfonyl C₁-C₄ hydrocarbyl group.
 16. The compound according to claim 15 corresponding in structure to Formula IV


17. The compound according to claim 15 corresponding in structure to Formula V

wherein R⁵ is selected from the group consisting of a C₁-C₄ hydrocarbyl, C₃-C₆ cyclohydrocarbyl, C₁-C₄ acylhydrocarbyl, and a sulfonyl C₁-C₄ hydrocarbyl group
 18. The compound according to claim 10 wherein said 5- or 6-membered divalent aromatic or heteroaromatic ring W is selected from the group consisting of a 1,2-phenylene, 2,3-pyridinylene, 3,4-pyridinylene, 4,5-pyridinylene, 2,3-pyrazinylene, 4,5-pyrimidinylene, and 5,6-pyrimidinylene group.
 19. The compound according to claim 10 corresponding in structure to Formula IIA


20. The compound according to claim 10 corresponding in structure to Formula IIIA


21. A compound corresponding to the formula


22. A compound corresponding to the formula


23. A process for treating a host mammal having a condition associated with pathological matrix metalloprotease activity that comprises administering a compound corresponding in structure to Formula I in an MMP enzyme-inhibiting effective amount to a mammalian host having such a condition:

wherein y and z are each zero or one and the sum of z+y is one; the ring structure W is a 5- or 6-membered divalent aromatic or heteroaromatic ring; R¹ is a substituent containing a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bonded directly to the depicted SO₂-group and having a length greater than about that of a hexyl group and less than about that of an eicosyl group, said R¹ defining a three-dimensional volume, when rotated about an axis drawn through the SO₂-bonded 1-position and the 4-position of a 6-membered ring radical or drawn through the SO₂-bonded 1-position and the center of 3,4-bond of a 5-membered ring radical, whose widest dimension in a direction transverse to the axis of rotation is about that of one furanyl ring to about that of two phenyl rings; R² and R³ are independently hydrido, C₁-C₄ hydrocarbyl, hydroxyl or amino, or R² and R³ together with the depicted carbon atom to which they are bonded form a 6-membered heterocyclic ring in which the heteroatom is oxygen, sulfur or nitrogen, said heteroatom being optionally substituted with one or two oxygens when sulfur and being optionally substituted with a moiety selected from the group consisting of a C₁-C₄ hydrocarbyl, C₃-C₆ cyclohydrocarbyl, C₁-C₄ acylhydrocarbyl, and a sulfonyl C₁-C₄ hydrocarbyl group when nitrogen.
 24. The process according to claim 21 wherein R¹ is a single-ringed cyclohydrocarbyl, heterocyclo, aryl or heteroaryl substituent that is 5- or 6-membered, and is itself substituted at its own 4-position when a 6-membered ring and at its own 3- or 4-position when a 5-membered ring with a substituent R⁴ selected from the group consisting of one other single-ringed aryl or heteroaryl group, a C₃-C₁₄ hydrocarbyl group, a C₂-C₁₄ hydrocarbyloxy group, a phenoxy group, a thiophenoxy group, an anilino group, a 4-thiopyridyl group, a phenylazo group, a phenylureido group, a nicotinamido group, an isonicotinamido group, a picolinamido group and a benzamido group.
 25. The process according to claim 21 wherein said R¹ substituent is PhR⁴ in which Ph is phenyl substituted with R⁴ at the 4-position, and R⁴ is a phenyl, phenoxy, anilino, thiophenoxy, phenylazo, benzamido, nicotinamido, isonicotinamido, picolinamido or phenylureido group
 26. The process according to claim 21 wherein said R¹ substituent is PhR⁴ in which Ph is phenyl substituted with R⁴ at the 4-position, and said R⁴ is a phenyl, phenoxy, anilino, thiophenoxy, phenylazo, benzamido, nicotinamido, isonicotinamido, picolinamido or phenylureido group that is substituted at the meta- or para-position or both with a moiety that is selected from the group consisting of a halogen, a C₁-C₉ hydrocarbyloxy group, a C₁-C₁₀ hydrocarbyl group, a di- C₁-C₉ hydrocarbylamino group, a carboxyl C₁-C₈ hydrocarbyl group, a C₁-C₄ hydrocarbyloxy carbonyl C₁-C₄ hydrocarbyl group, a C₁-C₄ hydrocarbyloxycarbonyl C₁-C₄ hydrocarbyl group and a carboxamido C₁-C₈ hydrocarbyl group, or is substituted at the meta- and para-positions by two methyl groups or by a methylenedioxy group.
 27. The process according to claim 21 wherein said R¹ substituent has a length greater than that of an octyl group and less than that of a stearyl group.
 28. The process according to claim 21 wherein said R³ is a phenoxy or thiophenoxy group that is unsubstituted.
 29. The process according to claim 21 wherein said compound is administered a plurality of times. 